Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof

ABSTRACT

A particulate SAE-CD composition is provided. The SAE-CD composition has an advantageous combination of physical properties not found in known solid forms of SAECD. In particular, the SAE-CD composition possesses an advantageous physicochemical and morphological property profile such that it can be tailored to particular uses. The SAE-CD composition of the invention has improved flow and dissolution performance as compared to known compositions of SAE-CD.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/448,411, filed Mar. 2, 2017, now U.S. Pat. No. 10,202,468, which is acontinuation of U.S. application Ser. No. 14/489,348, filed Sep. 17,2014, now U.S. Pat. No. 9,617,352, which is a continuation of U.S.application Ser. No. 13/243,956, filed Sep. 23, 2011, now U.S. Pat. No.8,846,901, which is a continuation of U.S. application Ser. No.12/108,228, filed Apr. 23, 2008, now U.S. Pat. No. 8,049,003, which is acontinuation of International Application No. PCT/US2005/038933, filedOct. 26, 2005, all of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to sulfoalkyl ether cyclodextrinderivatives having improved physical properties and to methods of makingthe same.

BACKGROUND OF THE INVENTION

The non-chemical physical property profile of a composition candramatically alter the in-process handling and performance, and possiblythe in vitro or in vivo performance, of a particular material. In otherwords, a given chemical composition having a first physical propertyprofile might be suitable for inhalation; whereas, the same chemicalcomposition having a different second physical property profile might beunsuitable for inhalation. Likewise, a particular excipient having afirst physical property profile might be better suitable for tablettingby compression than would be the same excipient having a differentsecond physical property profile.

For example, the suitability of different physical forms of a materialused as a carrier for dry powder inhalation will vary according to thenon-chemical physical property profile of the various physical forms ofthe material. The delivery of a drug by inhalation allows for depositionof the drug in different sections of the respiratory tract, e.g.,throat, trachea, bronchi and alveoli. Generally, the smaller theparticle size, the longer the particle will remain suspended in air andthe farther down the respiratory tract the drug can be delivered. Drugsare delivered by inhalation using a nebulizer, metered dose inhaler(MDI), or dry powder inhaler (DPI).

Dry powder inhalers provide powder pharmaceuticals in aerosol form topatients. In order to generate an aerosol, the powder in its staticstate must be fluidized and entrained into the patient's inspiratoryairflow. The powder is subject to numerous cohesive and adhesive forcesthat must be overcome if it is to be dispersed. Fluidization andentrainment requires the input of energy to the static powder bed. Theparticle size, shape, surface morphology and chemical composition ofcarrier particles can influence aerosol dispersion. Increased drugdispersion and deposition is generally observed with smaller carriersize and increased proportion of fine particles. Elongated carriersgenerally increased aerosol dispersibility and drug FPF (fine particlefraction), possibly due to increased duration in the airstream dragforces. Carriers with smooth surfaces produced higher respirablefractions. Low respirable fractions were obtained from carriers withmacroscopic surface roughness or smooth surfaces, whereas highrespirable fractions were obtained from carriers with microscopicsurface roughness, where smaller contact area and reduced drug adhesionoccurred at the tiny surface protrusions. Thus for dry powder inhalerformulations, the size of carrier particles should be selected on thebasis of a balance between these interrelated performancecharacteristics. Specifically, inter-particulate forces should be suchthat the drug particles adhere to the carrier (to aid in blending,uniformity, and allow the entrainment of drug into the inspiratoryair-stream), yet also allow detachment of the fine drug particles fromthe surface of the coarser carrier particles so that delivery to thelung can be facilitated. In view of the above, different physical formsof the known solid carrier lactose may or may not be suitable for drypowder inhalation.

The same general impact of physical form upon excipient behavior is truefor other pharmaceutical processes used to make dosage forms such as atablet, liquid, suspension, emulsion, film, laminate, pellet, powder,bead, granule, suppository, ointment, cream, etc. In other words, asingle excipient will need to be made in different physical forms inorder for it to be better suited for particular uses. For improvedtabletting by compression, for example, an excipient will preferablyhave improved flow. Good flow characteristics are desirable in order tofacilitate handling and processing in a tablet press or capsule-fillingmachine. It will also have a compressibility within a particular rangedepending upon the role of the excipient in the tablet. If an excipientis going to be used in a constitutable liquid formulation, the excipientwill preferably not clump when placed in the liquid and it will dissolvecompletely and quickly. Even though many of these are highly desiredfeatures in a solid excipient, it is very difficult to obtain any singleexcipient having all of these features. For this reason, among others,many different grades of excipients are developed in the pharmaceuticalindustry.

Drying methods such as tray drying, freeze drying, spray drying,fluidized bed spray granulation, and fluidized bed spray agglomeration,among others, are used in the pharmaceutical industry to prepare solidsfrom feed solutions, emulsions, suspensions or slurries. The physicalproperties of the isolated solid will depend upon the properties of thefeed material and the parameters employed in and the equipment used forthe drying method employed.

Spray drying entails atomizing a solids-containing feed solution orsuspension to form atomized droplets directed into a stream of hot gasin a drying chamber thereby evaporating the liquid carrier from thedroplets resulting in the formation of spherical particles. Fluidizedbed spray drying is a modified form of spray drying wherein a spraydrying process is performed in the presence of a fluidized bed(fluidized by the stream of hot gas) of fine particles such that theatomized droplets collide with and adhere to the fluidized particles. Bymodifying the solids content of the feed solution and in the dryingchamber, a spray drying apparatus can be made to agglomerate orgranulate the solids in a process called fluidized bed sprayagglomeration or fluidized bed spray granulation, respectively.Moreover, the use of a rectangular versus cylindrical spray dryingapparatus will have an impact upon the physical properties of theresulting product.

In an exemplary fluidized bed spray agglomeration/granulation with acylindrical apparatus, powder feed enters the solids feed inlet at acontrollable speed, and the liquid spray system sprays liquid feed fromthe top or bottom of the fluidized bed into the material. Heatedfluidizing gas flows upward from the inlet through the bottom screen,fluidizing the powder feed or seed particles in the fluidized-bedchamber. Simultaneously, classifying gas flows upward through thedischarge pipe at a velocity that's controlled to blow fine particlesback into the fluidized bed, allowing only larger particles with afalling velocity higher than the discharge pipe's classifying airvelocity to discharge through the pipe. This allows control of theproduct's particle size while keeping the product dust-free. Dustremoved from the exhaust air by the circular unit's external dedustingequipment can be recirculated to the recycle inlet for furtherprocessing. During this process, the smaller particles fuse with eachother or with larger particles to form agglomerates. As a result, theparticle size distribution of the particles in the fluidized bedincreases such that the percentage of fine particles present in theproduct is reduced as compared to the fluidized feed material.

Solubilization of poorly water soluble compounds in aqueous media isoften very difficult. Therefore, artisans have employed solubilizationenhancers, such as cyclodextrins, in the aqueous medium. Parent(underivatized) cyclodextrins and their derivatives are well knownexcipients that contain 6, 7, or 8 glucopyranose units and are referredto as α-, β-, and γ-cyclodextrin, respectively. Each cyclodextrinsubunit has secondary hydroxyl groups at the 2 and 3 positions and aprimary hydroxyl group at the 6-position. The cyclodextrins may bepictured as hollow truncated cones with hydrophilic exterior surfacesand hydrophobic interior cavities.

β-CD has been reportedly prepared in a variety of different forms usingdifferent finishing processes. American Maize Products (French patentNo. 2,597,485) recommends freeze-drying and spraying as suitable methodsfor recovering cyclodextrin ethers from aqueous solutions. However, thepowders obtained according to these various techniques have poordissolution. In addition, these powders do not flow easily and possessmediocre compression properties.

U.S. Pat. No. 6,555,139 to Sharma discloses a method for microfluidizingβ-CD in combination with a hydrophobic drug to yield a smooth,latex-like microsuspension.

U.S. Pat. No. 5,674,854 to Bodley et al. discloses a compositioncontaining an inclusion complex of β-CD and diclofenac. The compositioncan be prepared by spray agglomeration.

U.S. Patent Application Publication No. 20040234479 to Schleifenbaumdiscloses a flavor or fragrance containing a cyclodextrin particlecontaining the cyclodextrin particle and a flavor or fragrance, whereinthe cyclodextrin particle has a particle size in a range of 50 to 1000μ.The cyclodextrin particle comprises a cellulose ether and cyclodextrin,wherein the cyclodextrin particle is obtained by a single stagefluidized bed process from a spray mixture, and wherein a gasintroduction temperature is from 80° to 180° C. and a gas outlettemperature is from 40° to 95° C.

European Patent Application No. EP 392 608 describes a method forproducing powdered cyclodextrin complexes wherein the particle size isless than 12μ, preferably less than 5μ. Suitable processes for doing soinclude spray-drying and freeze-drying. The '608 application states thatsmall particle sizes of CD often exhibit reduced pourability orflowability and may dust easily. For this reason, the art suggests theuse of cyclodextrin complex particles having particle sizes of at least50μ.

U.S. Patent Application Publication No. 20030065167 to Lis et al.discloses a process for preparing a directly compressible β-CD. Theprocess includes “a step of dehydrating hydrated beta-cyclodextrin to awater content of less than 6%, preferably less than 4% and morepreferably still less than or equal to 2% by weight, followed by forcedrehydration to a water content greater than 10%, preferably greater than12% and more preferably still greater than or equal to 13% by weight.

The impact of the drying step or finishing step in the preparation ofhydroxypropyl-f-cyclodextrin (HP-β-CD) obtained from a syrup containingthe same has been explored. U.S. Patent Application Publication No.20030028014 to Sikorski et al. discloses an agglomerated HP-β-CD and aprocess from making the same. The agglomerated product is made in adouble drum dryer. It reportedly has low dusting and good dissolution inwater. The particle size of the product is about 30 to 200μ.

U.S. Pat. No. 5,756,484 to Fuertes et al. discloses a pulverulentHP-β-CD composition and a method for its preparation. The HP-β-CD has acentered particle size free of fine particles and an appreciablyimproved capacity to dissolve in aqueous medium. The HP-β-CD is made byspraying a solution of HP-β-CD on a moving pulverulent bed of HP-β-CDparticles.

The physical and chemical properties of the parent cyclodextrins can bemodified by derivatizing the hydroxyl groups with other functionalgroups. One such derivative is a sulfoalkyl ether cyclodextrin.

Sulfoalkyl ether cyclodextrin (SAE-CD) derivatives are well known as aretheir uses in a wide range of applications. SAE-CD derivatives areparticularly useful in solubilizing and/or stabilizing drugs. Asulfobutyl ether derivative of beta cyclodextrin (SBE-β-CD), inparticular the derivative with an average of about 7 substituents percyclodextrin molecule (SBE7-β-CD), has been commercialized by CyDex,Inc. as CAPTISOL®. The anionic sulfobutyl ether substituent dramaticallyimproves the aqueous solubility of the parent cyclodextrin. In addition,the presence of the charges decreases the ability of the molecule tocomplex with cholesterol as compared to the hydroxypropyl derivative.Reversible, non-covalent, complexation of drugs with CAPTISOL®cyclodextrin generally allows for increased solubility and stability ofdrugs in aqueous solutions.

CAPTISOL®, prepared by spray drying, is used in the commercialformulations VFEND® and GEODON®. It has become a leading cyclodextrinderivative for use in pharmaceutical formulations and thus is importantto the industry.

Methods of preparing SAE-CD derivatives are varied but generally includethe general steps of sulfoalkylation followed by isolation. The chemicalproperty profile of the SAE-CD is established during the sulfoalkylationstep. For example, altering reaction conditions during sulfoalkylationcan vary the average degree of substitution for and the averageregiochemical distribution of sulfoalkyl groups in the SAE-CD. The alkylchain length of the sulfoalkyl functional group is determined accordingthe sulfoalkylating agent used. And use of a particular alkalizing agentduring alkylation would result in formation of a particular SAE-CD salt,unless an ion exchange step were performed subsequent tosulfoalkylation.

In general, known processes for the sulfoalkylation step include, forexample: 1) exposure of underivatized parent cyclodextrin under alkalineconditions to an alkylating agent, e.g. alkyl sultone or ahaloalkylsulfonate; 2) optional addition of further alkalizing agent tothe reaction milieu to consume excess alkylating agent; and 3)neutralization of the reaction medium with acidifying agent. The vastmajority of literature processes conduct the sulfoalkylation step inaqueous media; however, some references disclose the use of pyridine,dioxane, or DMSO as the reaction solvent for sulfoalkylation. Literaturediscloses the use of an alkalizing agent in order to accelerate thesulfoalkylation reaction. Upon completion of the sulfoalkylation step,isolation and purification of the SAE-CD is conducted.

Several different isolation processes for SAE-CD followingsulfoalkylation and neutralization are described. In general, an aqueousliquid containing SAE-CD is dried to remove water to form a solid. Theliterature suggests various methods for removal of water from an aqueoussolution containing SAE-CD. Such methods include conventionalfreeze-drying, spray drying, oven drying, vacuum oven drying,roto-evaporation under reduced pressure, vacuum drying or vacuum drumdrying. See, for example, Ma (S.T.P. Pharma. Sciences (1999), 9(3),261-266), CAPTISOL® (sulfobutyl ether beta-cyclodextrin sodium;Pharmaceutical Excipients 2004; Eds. R. C. Rowe, P. J. Sheskey, S. C.Owen; Pharmaceutical Press and American Pharmaceutical Association,2004) and other references regarding the preparation of SAE-CDderivatives.

The art, therefore, is lacking teaching on the methods of preparing andusing SAE-CD derivatives having particular non-chemical physicalproperty profiles. Given the importance of SAE-CD to the pharmaceuticalindustry, it would be a significant improvement in the art to provideSAE-CD derivatives having particular non-chemical physical propertyprofiles so that such forms can be tailored for particular purposes.

SUMMARY OF THE INVENTION

The present invention seeks to overcome the disadvantages present inknown dry powder compositions of SAE-CD. As such, a derivatizedcyclodextrin-based, e.g., sulfoalkyl ether cyclodextrin (SAE-CD)-based,composition is provided. The present SAE-CD composition excludes aprincipal active agent. However, the composition possesses unexpectedlyadvantageous physical properties that exist as a result of the methodused to remove water from an aqueous medium containing SAE-CD. Thecomposition prepared by the process of the invention provides solidSAE-CD in particulate form.

The physical properties of the SAE-CD are modulated through a variety oftechniques to yield different grades of SAE-CD (a SAE-CD grade or SAE-CDcomposition) wherein each is adapted for use in specific dosage forms,such as a tablet, capsule, constitutable powder, dry powder inhaler,sachè, troche, and lozenge. The properties can also be modified forimproved handling, packaging, storage and other process relatedactivities. Also, the chemical properties can be adapted for particularuses by changing the identity of the counterion, changing the alkylchain length, average degree of substitution, or ring size of the parentcyclodextrin from which the SAE-CD is made. The properties can also beadapted for particular uses by changing the non-chemical physicalproperties of the SAE-CD such as by changing the mean or averageparticle diameter, the span of the particles size distribution, thewater content of the SAE-CD, the surface characteristics of the SAE-CDparticles, the rate of dissolution of the particles, the bulk density,the tap density, the Carr Index, compressibility, flowability and more.

The SAE-CD compositions of the invention possess numerous advantagesover known compositions of SAE-CD, i.e., those prepared according toknown methods that differ in the post-sulfoalkylation steps. The SAE-CDcompositions herein provide an unexpectedly improved aqueous dissolutionrate, compression crushing strength, ease of tabletting, and/or improvedsolids handling.

One form of a SAE-CD composition is provided containing no more thanabout 20% by wt. moisture. The SAE-CD composition can be included in adry formulation in admixture with an active agent such that all orsubstantially all of the active agent is not complexed with the SAE-CD.The SAE-CD composition can be included in a dry formulation in admixturewith one or more excipients. The SAE-CD composition can also be includedin a constitutable formulation.

The particulate SAE-CD compositions of the invention possessmorphological and physicochemical properties that predispose them todissolve more rapidly than previously known compositions of SAE-CD suchas those prepared by spray drying. The SAE-CD compositions, prepared bythe processes described herein, possess particular combinations ofmorphological and physicochemical properties. In some embodiments, theprocess is fluidized bed spray agglomeration. In some embodiments, theparticulate SAE-CD composition is prepared by fluidized bed spraygranulation, and the resulting SAE-CD composition possesses a differentcombination of physical properties than does a SAE-CD compositionprepared by fluidized bed spray agglomeration.

When SAE-CD particles are prepared by known methods, they do not possessthe advantageous combination of physical properties as that found in theSAE-CD composition of the invention. A SAE-CD composition disclosedherein is prepared by a process comprising:

providing an aqueous liquid feed comprising water and SAE-CD; and

subjecting the liquid feed to a combination fluidized bed spray dryingprocess whereby the SAE-CD is agglomerated (and/or granulated) and driedto below the point of deliquescence to form a particulate SAE-CDcomposition comprising agglomerated (and/or granulated) particleswherein at least 90% of the particle volume of the SAE-CD composition ismade of particles having calculated diameters greater than or equal toabout 25 microns. (The particle diameter cut-off for the 10% cumulativevolume fraction is 25 microns or greater.) The SAE-CD composition canpossess a tapped density in the range of about 0.66 to 0.75 g/cm³ orabout 0.49 to 0.75 g/cm³ when determined according to USP <616> Method 1and/or a bulk density in the range of about 0.55 to 0.66 g/cm³ or about0.38 to about 0.66 g/cm³ when determined according to USP <616>Method 1. For a specific SAE-CD composition, the tapped density ishigher than the bulk density.

The moisture content of the SAE-CD composition is below its point ofdeliquescence. However, particular embodiments include those having amoisture content of ≤18% by wt., ≤16% by wt., ≤15% by wt., ≤10% by wt.,or ≤5% by wt.

The SAE-CD composition is particulate and has a mean particle diameterof about 92 to about 200 microns, or less than or equal to about 110microns, or less than or equal to about 200 microns. The mean particlediameter has been determined according to Example 3 with a Malverninstrument. This instrument measures particle diameter via low anglelaser light scattering and calculates particle diameter based upon thevolume of an assumed spherical shape. The term “mean particle diameter”is defined as the volume moment mean, otherwise known as the DeBrouckere mean diameter, D[4,3]. The SAE-CD composition can be preparedby fluidized bed spray agglomeration or fluidized bed spray granulation.

The SAE-CD composition has a combination of physical properties thatrender it better suited than previously known SAE-CD compositions foruse in compressed tablet formulations. For example, the SAE-CDcomposition has a compression crushing strength in the range of about1.0 to about 20 kP when 200 mg of SAE-CD composition are compressed intoa tablet having a diameter of 0.345 inches using a Pmax (peakcompression pressure) in the range of about 30 to about 275 MPa and theSAE-CD composition has a moisture content in the range of about 2 toabout 3% by wt. as determined by LOD. Alternatively, the SAE-CDcomposition has a compression crushing strength in the range of about0.5 to 11 KP when 200 mg of SAE-CD composition are compressed into atablet having a diameter of 0.345 inches using a Pmax MPa in the rangeof about 15-70 MPa and the SAE-CD has a moisture content in the range ofabout 5-6% by wt.

The SAE-CD composition possesses a more rapid dissolution rate in waterthan does SAE-CD prepared by conventional spray drying. When 2.5 g ofSAE-CD composition is assayed according to Example 6, it has an averagedissolution time of 2.5 minutes or less, or 4.5 minutes or less, or 3.5minutes or less when placed in water.

A SAE-CD composition having an advantageous flow property is provided bythe invention. For example, the SAE-CD composition has agravitational-flow minimum orifice diameter of about 3-7 mm or 4-6 mm,or less than about 10 mm or less than about 20 mm. The method of Example5 can be followed to determine the gravitational-flow minimum orificediameter.

Density of the SAE-CD composition can be controlled. The SAE-CDcomposition has a true density of 1.25 to 1.35 g/cm³ or 1.1 to 1.5g/cm³. Embodiments of the SAE-CD composition include those having a bulkdensity of about 0.55 to about 0.66 g/cm³, about 0.38 to less than about0.55 g/cm³, or about 0.38 to about 0.66 g/cm³ when performed accordingto USP <616> Method 1. Other embodiments have a tap density (tappeddensity) of about 0.66 to about 0.75 g/cm³, or about 0.49 to about 0.66g/cm³ or about 0.49 to about 0.75 g/cm³ when performed according to USP<616> Method 1. Additionally or alternatively, the SAE-CD compositionhas a CARR's index of less than or about 24% or less than or about 18%or less than or about 16%.

Another aspect of the invention provides a SAE-CD composition having amoisture content below its point of deliquescence, a bulk density in therange of about 0.55 to 0.66 g/cm³, and a tapped density in the range ofabout 0.66 to 0.75 g/cm³, a CARR's index of less than or about 24%; andoptionally, a moisture content of less than about 18% by wt., optionallya true density in the range of about 1.1 to 1.5 g/cm³, optionally agravitational-flow minimum orifice diameter of less than about 20 mm,optionally, wherein the SAE-CD composition is prepared by fluidized bedspray agglomeration or fluidized bed spray granulation.

Another aspect provides for the use of the SAE-CD compositions astabletting excipients, capsule excipients, DPI (dry powder inhaler)excipients, extrusion excipients, PMDI (pressurized metered doseinhaler) excipients, carriers for delivery of a drug via a DPI or PMDI,orodispersible tablet excipients, ingestible powders, dry granulationexcipients, pelletizing excipients, non-pariel seeds, aerosolizablepowders, and/or constitutable powder excipients.

The SAE-CD composition can be included in a formulation (e.g. solid,liquid, gel, suspension, emulsion, or other known formulation)comprising one or more active agents and, optionally, one or moreexcipients. Therefor, the invention also provides a method of treatingdiseases or disorders by administration to a subject of the SAE-CDcomposition in a formulation further comprising an active agent.

In one embodiment, the properties of the SAE-CD composition can bemodulated such that different physicochemical properties are matched todrug particle properties for optimizing dispersion from dry powderinhalers.

Additional embodiments of the invention include those wherein: 1) theSAE-CD composition is a compound of the formula 1 or a mixture thereof;2) a formulation containing the SAE-CD composition further comprises anantioxidant, acidifying agent, alkalizing agent, buffering agent,solubility-enhancing agent, penetration enhancer, electrolyte,fragrance, glucose, glidant, stabilizer, bulking agent, cryoprotectant,plasticizer, flavors, sweeteners, surface tension modifier, densitymodifier, volatility modifier, or a combination thereof; and/or 3) theSAE-CD is a compound of the formula 2 or a mixture thereof.

Another aspect of the invention provides an improved solid formulation,the improvement comprising including in the formulation a SAE-CDcomposition of the invention, wherein the SAE-CD has been prepared by afluidized bed spray drying process (agglomeration or granulation) or aSAE-CD composition possessing a physical property profile as definedherein. These and other aspects of this invention will be apparent uponreference to the following detailed description, examples, claims andattached figures.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are given by way of illustration only, and thusare not intended to limit the scope of the present invention.

FIG. 1 depicts a SEM (scanning electron microscope) photograph of anexemplary batch of SAE-CD composition made according to the invention.The SAE-CD particles were made according to differentpost-sulfoalkylation processes.

FIG. 2 depicts the general layout of an exemplary fluidized bed spraydryer.

FIG. 3 depicts the general layout of another exemplary fluidized bedspray dryer.

FIG. 4 is a graph depicting the relationship between crushing strengthand compression pressure for SAE-CD compositions of the inventioncontaining differing amounts of moisture.

DETAILED DESCRIPTION OF THE INVENTION

The compositions of SAE-CD are adapted for use in particularapplications. When used in those applications, the present compositionsof SAE-CD are advantageous over and provide improved performance overpreviously known compositions of SAE-CD for those applications. Byvarying the finishing conditions (post-sulfoalkylation steps; stepsoccurring subsequent to the sulfoalkylation step), one is able to modifythe physicochemical and morphological properties of the SAE-CD. Forexample, different SAE-CD compositions can be obtained by varying thedrying and isolation conditions.

Even though the SAE-CD composition of the invention does not requireattritting, it can be attritted to provide even further modified SAE-CDcompositions. For example, attritting an SAE-CD composition prepared byfluidized bed spray drying can result in an SAE-CD composition having adifferent bulk density, tapped density, and/or particle diameter. Asused herein, the term attritting means to physically abrade a solid toreduce its particle size. Any such process used in the pharmaceuticalindustry is suitable for use in the process of the invention. Attritionprocesses include, by way of example and without limitation,micronizing, ball milling, jet milling, hammer milling, pin milling,tumbling, sieving, and mortar and pestle. Both low and high energymethods can be used.

The present invention provides a “SAE-CD composition”, meaning acomposition of sulfoalkyl ether cyclodextrin having a combination ofdifferent physical properties and excluding an active agent orpharmaceutical excipient. As regards the SAE-CD composition, the term“excluding” means not purposefully added. Therefore, it is possible forthe SAE-CD composition to contain excipients endogenous to its method ofmanufacture. For example, a first SAE-CD composition will have a firstcombination of physical properties, i.e. a first physical propertyprofile, and the second SAE-CD composition will have a secondcombination of physical properties. By virtue of the differentcombinations of physical properties, the first SAE-CD composition willbe more advantageous for a particular use, and the second SAE-CDcomposition will be more advantageous for another particular use.

The present invention provides SAE-CD compositions, wherein the SAE-CDis a compound of the Formula 1, or a combination thereof:

-   wherein:-   n is 4, 5 or 6;-   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are each, independently, —O—    or a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, wherein at least one of R₁ to    R₉ is independently a —O—(C₂-C₆ alkylene)-SO₃ ⁻ group, preferably a    —O—(CH₂)_(m)SO₃ ⁻ group, wherein m is 2 to 6, preferably 2 to 4,    (e.g. —OCH₂CH₂CH₂SO₃ ⁻ or —OCH₂CH₂CH₂CH₂SO₃ ⁻); and-   S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈ and S₉ are each, independently, a    pharmaceutically acceptable cation which includes, for example, H⁺,    alkali metals (e.g. Li⁺, Na⁺, K⁺), alkaline earth metals (e.g.,    Ca⁺², Mg⁺²), ammonium ions and amine cations such as the cations of    (C₁-C₆)-alkylamines, piperidine, pyrazine, (C₁-C₆)-alkanolamine and    (C₄-C₈)-cycloalkanolanline.

Suitable methods for preparing a SAE-CD raw material for use inpreparing the SAE-CD composition of the invention are disclosed U.S.Pat. Nos. 5,376,645, 5,874,418, and 5,134,127 to Stella et al.; U.S.Pat. No. 3,426,011 to Pamerter et al.; Lammers et al. (Recl. Trav. Chim.Pays-Bas (1972), 91(6), 733-742); Staerke (1971), 23(5), 167-171); Qu etal. (J. Inclusion Phenom. Macro. Chem., (2002), 43, 213-221); U.S. Pat.No. 5,241,059 to Yoshinaga; U.S. Pat. No. 6,153,746 to Shah; PCTInternational Publication No. WO 2005/042584 to Stella et al.: Adam etal. (J. Med. Chem. (2002), 45, 1806-1816); PCT International PublicationNo. WO 01/40316 to Zhang et al.; Tarver et al. (Bioorganic & MedicinalChemistry (2002), 10, 1819-1827); Ma (S.T.P. Pharma. Sciences (1999),9(3), 261-266); Jung et al. (J. Chromat. 1996, 755, 81-88); and Luna etal. (Carbohydr. Res. 1997, 299, 103-110), the entire disclosures ofwhich are hereby incorporated by reference.

The SAE-CD raw material is included in the liquid feed used in thefluidized bed spray drying process employed to prepare an SAE-CDcomposition of the invention.

The SAE-CD composition of the invention can also include a combinationof derivatized cyclodextrin (SAE-CD) and underivatized cyclodextrin. Forexample, a SAE-CD composition can be made to include underivatizedcyclodextrin in the amount of 0 to less than 50% by wt. of the totalcyclodextrin present. Exemplary embodiments of the SAE-CD compositioninclude those comprising 0-5% by wt., 5-50% by wt., less than 5%, lessthan 10%, less than 20%, less than 30%, less than 40%, or less than 50%underivatized cyclodextrin.

The terms “alkylene” and “alkyl,” as used herein (e.g., in the—O—(C₂-C₆-alkylene)SO₃ ⁻ group or in the alkylamines), include linear,cyclic, or branched, and saturated or unsaturated (i.e., containing onedouble bond) divalent alkylene groups or monovalent alkyl groups,respectively. The term “alkanol” in this text likewise includes bothlinear, cyclic and branched, saturated and unsaturated alkyl componentsof the alkanol groups, in which the hydroxyl groups may be situated atany position on the alkyl moiety. The term “cycloalkanol” includesunsubstituted or substituted (e.g., by methyl or ethyl) cyclic alcohols.

Some embodiments of the present invention provide compositionscontaining a single type of cyclodextrin derivative having the structureset out in formula (I), where the composition overall contains on theaverage at least 1 and up to 3n+6 alkylsulfonic acid moieties percyclodextrin molecule. The invention also includes compositionscontaining cyclodextrin derivatives having a narrow or wide range fordegree of substitution and high or low degree of substitution. Thesecombinations can be optimized as needed to provide cyclodextrins havingparticular properties.

Exemplary SAE-CD derivatives include SBE4-β-CD. SBE7-β-CD, SBE11-β-CD,SBE7-γ-CD and SBE5-γ-CD which correspond to SAE-CD derivatives of theformula 1 wherein n=5, 5, 5, 6 and 6, respectively; m is 4; and thereare on average 4, 7, 11, 7 and 5 sulfoalkyl ether substituents present,respectively. Other exemplary SAE-CD derivatives include those of theformula SAEx-R-CD (Formula 2), wherein SAE is sulfomethyl ether (SME),sulfoethyl ether (SEE), sulfopropyl ether (SPE), sulfobutyl ether (SBE),sulfopentyl ether (SPtE), or sulfohexyl ether (SHE); x (average orspecific degree of substitution) is 1-18, 1-21, 1-24, when R (ringstructure of parent cyclodextrin) is α, β or γ, respectively; and CD iscyclodextrin. The SAE functional group includes a cationic counterion asdisclosed herein or generally as used in the pharmaceutical industry forthe counterion of any acidic group.

Since SAE-CD is a poly-anionic cyclodextrin, it can be provided indifferent salt forms. Suitable counterions for the SAE functionalgroup(s) include cationic organic atoms or molecules and cationicinorganic atoms or molecules. The SAE-CD can include a single type ofcounterion or a mixture of different counterions. The properties of theSAE-CD can be modified by changing the identity of the counterionpresent. For example, a first salt form of SAE-CD can have a greaterelectrostatic charge than a different second salt form of SAE-CD. Thecalcium salt form has been found to be more electronegative than thesodium salt form. Likewise, a SAE-CD having a first degree ofsubstitution can have a greater electrostatic charge than a secondSAE-CD having a different degree of substitution.

When the SAE-CD composition is intended for intra-pulmonaryadministration, the median particle diameter can be in the range ofabout 0.1 to about 10 microns or about 0.5 to about 6.4 microns. If itis desired that the particles reach the lower regions of the respiratorytract, i.e., the alveoli and terminal bronchi, the median particlediameter size range can be in the range of about 0.5 to about 2.5microns. If it is desired that the particles reach the upper respiratorytract, the particle diameter size range can be between 2.5 microns and10 microns. A SAE-CD composition with this median particle diameter sizecan be prepared by attritting a SAE-CD composition having a largermedian particle diameter size range.

The particle diameter span (defined as the ratio=(mean particle diameterof the 90^(th) percentile−mean particle diameter of 10^(th)percentile)/mean particle diameter of the 50^(th) percentile) of theSAE-CD composition can also impact its performance. SAE-CD having broad,moderate and narrow particle size distribution may be used in theinvention. A larger span indicates a broader particle size distributionand a smaller span indicates a narrower particle size distribution.Specific embodiments include those wherein the span is in the range ofabout 1.5 to 2.9, 1.1 to 1.9, or 1.4 to 1.7.

Since particles are present as a distribution of sizes, the distributioncan be monomodal, bimodal or polymodal, the preferred being monomodaldistribution.

The SAE-CD composition is a particulate composition containingagglomerated and non-agglomerated particles. Agglomerated particles canbe prepared by fluidized bed spray drying, which can includeagglomeration and/or granulation. The term agglomeration, which can beused interchangeably with granulation, is taken to mean a process inwhich dispersed fine particles in a composition are fused with otherparticles in the composition to form a coarser particulate compositionthereby reducing the amount of fine particles and increasing the overallmean particle diameter of the composition. The collection of particlesthat results can be called an agglomerate or granulate. The SAE-CDcomposition of the invention is distinguishable by SEM from othercompositions of SAE-CD made according to other processes. FIG. 1 depictsa SEM of an exemplary SAE-CD composition made by fluidized bed spraydrying. The particles have a rough surface texture and comprise asubstantial amount of agglomerated particles.

Exemplary processes for the preparation of the SAE-CD compositioninclude fluidized bed spray agglomeration or fluidized bed spraygranulation.

FIG. 2 depicts an exemplary fluidized bed spray dryer system that can beused to prepare a SAE-CD composition of the invention. This systemincludes a liquid feed tank (1), cylindrical fluidized bed spray dryingunit (2), cyclone particle classifier (3), finished-product collectioncontainer (4), gas filtration unit (5), waste-product collectioncontainer (6), condensers (7), and fluidized bed chambers (8-10). Thesystem can be operated as follows. To begin the process, an aqueousliquid feed containing SAE-CD raw material is transferred from the tank(1) to the dryer (2) via conduit (M). The liquid feed is atomized intothe drying chamber in a counter-current manner against the hot gasstream (A) to form an initial fluidized bed of particles. The fineparticles formed exit the drying chamber and are conducted via conduit(B) to the cyclone (3), which classifies the particles and returnsappropriately-sized fine particles via conduit (C) back into the upperportion of the drying chamber at a location adjacent to and in aco-current fashion with the liquid feed. As additional liquid feed isatomized into the drying chamber larger particles and fine particles areformed, and the larger particles (those not considered “fine” particles)form the fluidized bed in chamber (8). When the particles reach theintended mean particle diameter size, they are conducted to chamber (9),and subsequently, chamber (10). Each chamber includes its own gas inletand contains a fluidized bed of particles. The gas inlet for chamber (8)is the main hot gas stream (A) that fluidizes the bed of particles inthe drying chamber (8). The gas stream (N) for chamber (9) is lower intemperature than the stream (A), and the stream (P) is even lower intemperature. As the particles move from chamber (8) to chamber (9) andthen chamber (10), they are cooled. The finished SAE-CD composition iscollected from chamber (10) and conducted to the container (4) via aconduit (F). Fine particles present in chambers (9) and (10) areconducted via conduit (G) to the cyclone (3). Gas exiting the cyclone isconducted via conduit (H) into the filter unit (5) to collect anyparticles not otherwise recycled by the cyclone to the drying chamber.Particles collected in the filter unit are loaded into a collectioncontainer (6) for possible reprocessing. Gas exits the filter unit andis conducted through the condenser(s) (7), which remove moisture fromthe gas. Finally, the gas is either vented or returned back to thedrying chamber via conduit (L) and/or the gas streams (A, N, or P).

FIG. 3 depicts another exemplary fluidized bed spray dryer system thatcan be used to prepare a SAE-CD composition of the invention. Thissystem is similar to that of FIG. 2; however, it excludes the chambers(9-10), the particle-recycle conduit (G), and the condenser(s) (7).Moreover, the cyclone returns the fine particles to the drying chambervia conduit (C) and subsequently conduit (C1) and/or conduit (C2). Whenthe fines are introduced into the drying chamber via the conduit (C1),they are introduced in a co-current manner with the flow of liquid feedbeing atomized into the drying chamber. When the fines are introducedinto the drying chamber via the conduit (C2), the fines are introducedin a direction that is tangential to or perpendicular to the flow of gasstream (A) being introduced into the drying chamber and/or the gas inlet(L). Note that this exemplary system does not return gas from thefiltration unit back into the drying chamber; however, it can bemodified to do so.

Most particles in such fluidized bed chambers typically do not reach theheight of the cloud of atomized liquid feed. However, fine particlesformed during the process that are recycled back into the drying chambercan be introduced at a location adjacent the liquid feed atomizer or ata location between the atomizer and the fluidized bed.

During operation of either system, the flow of gas stream can beadjusted at various locations within the system in order to modify bedfluidization, drying rate, fines classification, and/or feed rate of thefines into the drying chamber. Fluidized bed spray drying processincludes:

providing a liquid feed (solution, suspension or slurry) comprising aliquid carrier and optionally SAE-CD;

providing in a drying chamber a fluidized bed of SAE-CD particles havinga first mean particle diameter size, wherein the bed is fluidized with astream of hot gas flowing in a first direction;

atomizing the liquid feed onto the fluidized bed in the drying chamberto form a particulate SAE-CD composition comprising agglomeratedparticles having a greater second mean particle diameter size, whereinthe atomization is conducted in a second direction and a majority of theliquid carrier has been removed from the particulate composition; and

collecting the particulate composition to form the SAE-CD composition.

Specific embodiments of the processes include those wherein: 1) theprocess further comprises recycling a portion of the smaller particlesin the particulate composition back to the drying chamber, 2) therecycled portion of particles is introduced into the drying chamber at alocation adjacent the point of introduction of the liquid feed; 3) therecycled portion of particles is introduced into the drying chamber in adirection tangential or perpendicular to the direction of introductionof the liquid feed into the drying chamber, 4) the recycled portion ofparticles is introduced into the drying chamber at a location adjacentthe cone of the drying chamber; 5) the process is conducted in aco-current manner; 6) the process is conducted in a counter-currentmanner; 7) the process is conducted in a mixed flow manner, 8) theparticulate composition comprises less than 18% by wt. of liquidcarrier, 9) the liquid carrier is aqueous; 10) the liquid feed comprisesSAE-CD; 11) the SAE-CD composition possesses a combination of physicalproperties as described herein; and 12) the fluidized bed spray dryerhas a cylindrical and/or conical drying chamber.

In a co-current fluidized bed spray drying process, the direction offlow of the atomized liquid feed in the drying chamber is the same asthe direction of flow of the hot air used to fluidize the bed ofparticles. The atomizer can be a spray nozzle or a rotary atomizer (e.g.rotating disk). The air current can be controlled such that laminar orturbulent flow occurs predominantly.

In a counter-current fluidized bed spray drying process, the hot airused to fluidize the bed moves through the drying chamber in a directionopposite that of the atomized liquid feed.

In a mixed flow fluidized bed spray drying process, particles movethrough the drying chamber in both co-current and counter-currentphases. This mode requires the use of a nozzle atomizer spraying upwardsinto an incoming airflow or an atomizer spraying droplets downwardstowards an integrated fluid bed, wherein the air inlet and outlet arelocated at the top of the drying chamber. Additional air inlets willdirect flow upwards to fluidize the bed of particles.

The fine or small particles used to form the fluidized bed in the dryingchamber can be prepared separately such as by spray drying, milling,grinding, otherwise attritting, sieving, or other suitable means.Otherwise, the fine particles can be prepared in situ by operating theequipment as a conventional spray dryer and subsequently operating theequipment as a fluidized bed spray dryer. In one embodiment, the fine orsmall particles are obtained by separating those particles from thematerial removed from the drying chamber and recycling the fine or smallparticles back into the drying chamber. The invention includes processeswhereby the fine particles are introduced into the drying chamber and/orare generated in situ by virtue of drying of the atomized liquid feed.

The process of the invention can be run in a continuous orsemicontinuous manner whereby liquid feed containing SAE-CD raw materialis introduced into the drying chamber continuously or semicontinuouslyand SAE-CD composition is removed from the fluidized bed continuously orsemicontinuously.

The aqueous liquid carrier used in the liquid feed, which can be asolution or slurry, may or may not contain another material, such asby-product(s) of the sulfoalkylation reaction and subsequentbasification of the reaction milieu. As used herein, a liquid carrier isany aqueous medium used in the pharmaceutical sciences used toagglomerate or granulate solids.

The SAE-CD solids content of the liquid feed can range from 0.1 to 80%by wt., 10 to 70% by wt., 30 to 70% by wt., or 40 to 60% by wt. solids.Some embodiments of the liquid feed comprise: 1) only sulfoalkyl ethercyclodextrin and water; or 2) only sulfoalkyl ether cyclodextrin, waterand by-products of the synthetic process used to prepare the sulfoalkylether cyclodextrin. The sulfoalkyl ether cyclodextrin used in the liquidfeed is sometimes referred to herein as the sulfoalkyl ethercyclodextrin raw material.

The liquid feed can be cooled or heated prior to entry into the dryingchamber. Temperature can be used to control viscosity of the liquidfeed: the higher the temperature, the lower the viscosity. Thetemperature of the liquid feed can be 0° C. to 100° C. or ambienttemperature to 70° C.

The gas used to conduct particles throughout the system is generally agas such as air, helium, or nitrogen. The system can include agas-charging unit to load gas for operation, purging andsupplementation.

The temperature of the inlet gas can be used to control drying rate ofthe particles, production rate, extent of agglomeration, water contentof the SAE-CD composition and/or type of agglomeration. The temperaturecan vary from about 100° to about 300° C., about 130° to about 180° C.,about 150° to about 170° C., or about 210° to about 250° C.

The SAE-CD composition has a gravitational-flow minimum orifice diameterranging from about 3-7 mm or 4-6 mm, or less than about 10 mm or lessthan about 20 mm. The term “gravitational-flow minimum orifice diameter”means the minimum diameter of an orifice through which the SAE-CDcomposition will provide an acceptable bulk flow. The example belowfurther defines the term. This parameter is determined according to themethod of Example 5 wherein a FLOWDEX (Hanson Research Corp.,Northridge, Calif.) apparatus is used. The present inventors havesucceeded in preparing a SAE-CD composition that has a substantiallydifferent minimum orifice diameter than has been prepared byconventional spray drying.

The SAE-CD composition has a CARR's index of less than or about 24%compressibility or less than or about 18% compressibility or less thanor about 16% compressibility. As used in this regards, “compressibility”refers to the relative percent reduction that a particulate mass willundergo during the tapped density determination. The CARR's index is ameasure of the compressibility of a SAE-CD composition. It is based uponthe bulk and tapped density of the material. The CARR's index has beendetermined according to Example 8 below. The present inventors havesucceeded in preparing a spray agglomerated SAE-CD composition having aCARR's index substantially different to other SAE-CD compositionsprepared by spray drying, freeze-drying, or spray agglomeration.

The SAE-CD has a true density in the range of about 1.25 to 1.35 g/cm³or 1.1 to 1.5 g/cm³ or 1.29 to 1.32 g/cm³. True density has beendetermined according to Example 8 below. The SAE-CD composition of theinvention has a substantially different true density than a SAE-CDcomposition prepared by spray drying.

The SAE-CD composition has a bulk density of about 0.55 to 0.66 g/cm³,about 0.38 to less than 0.55 g/cm³, or about 0.38 to about 0.66 g/cm³.The SAE-CD composition made according to the spray agglomeration processof the invention has a higher bulk density than that of a SAE-CDcomposition made by another spray dry agglomeration process.

The SAE-CD composition has a tapped density (tap density) of about 0.66to 0.75 g/cm³, or about 0.49 to 0.66 g/cm³ or about 0.49 to about 0.75g/cm³ when performed according to USP <616> Method 1. The SAE-CDcomposition made according to the spray agglomeration process of theinvention has a higher tap density than that of a SAE-CD compositionmade by another spray dry agglomeration process.

Since solid SAE-CD composition can be used for the manufacture oftablets, especially compressed tablets, its compression crushingstrength at different peak compression pressures was determined withSAE-CD compositions having different moisture contents. The method ofExample 7 was used to determine this relationship. SAE-CD compositionperformance was compared (FIG. 4) to that of Avicel PH-200, lactose andDical, which are three excipients commonly used in the manufacture oftablet formulations. The SAE-CD composition of the invention is highlyadvantageous, as its compression behavior can be improved by changingits moisture content, particle size and/or particle shape.

Tablet Hardness or Tablet Crushing Strength in units of kiloponds (kP)versus Peak Compression Pressure (Pmax) in units of megapascals (MPa) ispresented for SAE-CD composition (SBE7-β-CD) sample (B3, B4) of thisinvention used ‘as is’, i.e. as obtained from the fluidized bed spraydrying process, and equilibrated (B3 Eq and B4 Eq) over saturatedmagnesium nitrate. The performance of those samples was compared to thatof commercial direct compression bulk excipients, e.g. microcrystallinecellulose or MCC (Avicel PH 200, FMC), lactose monohydrate (SuperTab,The Lactose Co. of New Zealand), dibasic calcium phosphate dihydrate(Emcompress, Penwest Pharm Co.). For the tooling used in this study, 100MPa is approximately equivalent to 6 kN of force. The ‘as is’ watercontent of the SAE-CD composition of this invention was 2.77% and 2.36%for B3 and B4, respectively, as determined by Loss on Drying (LOD) at110 C via Computrac Model 2000XL (Arizona Instruments, Tempe, Ariz.).The water content after equilibration as determined by LOD was 5.46% and5.50% for B3 Eq and B4 Eq, respectively.

At lower levels of moisture content, e.g. in the range of about 2 toabout 3% by wt. (as determined by LOD run at 104° to 110° C.), theSAE-CD composition had a compression crushing strength in the range ofabout 1 to about 20 kP (kiloponds) when compressed into a tablet using aPmax (peak compression pressure) in the range of about 30 to about 275MPa (megapascals). At higher levels of moisture content, e.g. in therange of about 5 to about 6% by wt. (as determined by LOD), the SAE-CDcomposition had a compression crushing strength in the range of about0.5 to about 11 kP when compressed into a tablet using a Pmax in therange of about 15 to about 70 MPa. The mean particle diameter, particlediameter size distribution, and morphology of the SAE-CD composition arereadily modified to match the wide variety of micronized drugcharacteristics that are presented to a formulator of the art. Anadvantage of the present invention is the ability of an artisan tomodulate the physicochemical properties of the SAE-CD composition tomatch or complement formulation or manufacturing processes, drugproperties or excipient properties thereby resulting in an optimalproduct.

The dosage form of the invention can be used to administer a wide rangeof active agents. Active agents generally include physiologically orpharmacologically active substances that produce a systemic or localizedeffect or effects on animals and human beings. Active agents alsoinclude pesticides, herbicides, insecticides, antioxidants, plant growthinstigators, sterilization agents, catalysts, chemical reagents, foodproducts, nutrients, cosmetics, vitamins, minerals, dietary supplements,sterility inhibitors, fertility instigators, microorganisms, flavoringagents, sweeteners, cleansing agents and other such compounds forpharmaceutical, veterinary, horticultural, household, food, culinary,agricultural, cosmetic, industrial, cleaning, confectionery andflavoring applications.

The active agent can be independently selected at each occurrence frompharmaceutical active agents such as an antibiotic agent, antihistamineagent, decongestant, anti-inflammatory agent, antiparasitic agent,antiviral agent, local anesthetic, antifungal agent, antibacterialagent, amoebicidal agent, trichomonocidal agent, analgesic agent,anti-arthritic agent, anti-asthmatic agent, anticoagulant agent,anticonvulsant agent, antidepressant agent, antidiabetic agent,antineoplastic agent, anti-psychotic agent, neuroleptic agent,antihypertensive agent, hypnotic agent, sedative agent, anxiolyticenergizer agent, anti-Parkinson's disease agent, anti-Alzheimer'sdisease agent, muscle relaxant agent, antimalarial agent, hormonalagent, contraceptive agent, sympathomimetic agent, hypoglycemic agent,anti-hyperglyceridemia agent, anti-dyslipidemia agent, cholesterolreducing agent, bile acid absorption inhibitor, antilipemic agent,ophthalmic agent, electrolytic agent, diagnostic agent, prokineticagent, gastric acid secretion inhibitor agent, anti-ulcerant agent,anti-flatulent agent, anti-incontinence agent, cardiovascular agent,corticosteroid, B₂ adrenoreceptor agonist, dopamine D₂ receptor agonist,anticholinergic agent, IL-5 inhibitor, antisense modulators of IL-5,milrinone lactate, tryptase inhibitor, tachykinin receptor antagonist,leukotriene receptor antagonist, 5-lypoxygenase inhibitor, anti-IgEantibody, protease inhibitor or a combination thereof.

Other specific active agents that can be employed according to theinvention include pentamidine isethiouate, albuterol sulfate,metaproterenol sulfate, flunisolide, cromolyn sodium, sodiumcromoglycate, ergotamine tartrate, levalbuterol, terbutaline,reproterol, salbutamol, salmeterol, formoterol, fenoterol, clenbuterol,bambuterol, tulobuterol, broxaterol, epinephrine, isoprenaline orhexoprenaline, an anticholinergic, such as tiotropium, ipratropium,oxitropium or glycopyrronium; a leukotriene antagonist, such asandolast, iralukast, pranlukast, imitrodast, seratrodast, zileuton,zafirlukast or montelukast; a phosphodiesterase inhibitor, such asfilaminast or piclamilast; a paf inhibitor, such as apafant, forapafantor israpafant; a potassium channel opener, such as amiloride orfurosemide; a painkiller, such as morphine, fentanyl, pentazocine,buprenorphine, pethidine, tilidine, methadone or heroin; a potencyagent, such as sildenafil, alprostadil or phentolamine; a peptide orprotein, such as insulin, erythropoietin, gonadotropin or vasopressin;calcitonin, factor ix, granulocyte colony stimulating factor,granulocyte macrophage colony, growth hormone, heparin, heparin (lowmolecular weight), interferon alpha, interferon beta, interferon gamma,interleukin-2, luteinizing hormone releasing hormone, somatostatinanalog, amylin, ciliary neurotrophic factor, growth hormone releasingfactor, insulin-like growth factor, insulinotropin, interleukin-1receptor antagonist, interleukin-3, interleukin-4, interleukin-6,macrophage colony stimulating, factor (m-csf), nerve growth factor,parathyroid hormone, thymosin alpha 1, iib/iiia inhibitor, alpha-1antitrypsin, anti-rsv antibody, cystic fibrosis transmembrane regulator(cftr) gene, deoxyribonuclase (dnase), bactericidal/permeability (ards),increasing protein anti-cmv antibody, interleukin-1 receptor, or apharmaceutically acceptable derivative or salt of these compounds.

The active agents (drugs) listed herein should not be consideredexhaustive and is merely exemplary of the many embodiments consideredwithin the scope of the invention.

Many other active agents can be administered with the composition of thepresent invention. Suitable drugs are selected from the list of drugsincluded herein as well as from any other drugs accepted by theU.S.F.D.A. or other similarly recognized authority in Canada (HealthCanada). Mexico (Mexico Department of Health), Europe (EuropeanMedicines Agency (EMEA)), South America (in particular in Argentina(Administración Nacional de Medicamentos, Alimentos y Tecnologfa Médica(ANMAT) and Brazil (Ministério da Saúde)), Australia (Department ofHealth and Ageing), Africa (in particular in South Africa (Department ofHealth) and Zimbawe (Ministry of Health and and Child Welfare),) or Asia(in particular Japan (Ministry of Health, Labour and Welfare), Taiwan(Executive Yuans Department of Health), and China (Ministry of HealthPeople's Republic of China)) as being suitable for administration tohumans or animals. Some embodiments of the invention include thosewherein the active substance is pharmacologically or biologically activeor wherein the environment of use is the GI tract of a mammal.

The active agent can be present in its neutral, ionic, salt, basic,acidic, natural, synthetic, diastereomeric, epimeric, isomeric,enantiomerically pure, racemic, solvate, hydrate, anhydrous, chelate,derivative, analog, esterified, non-esterified, or other common form.Whenever an active agent is named herein, all such forms available areincluded.

An active agent contained within the present formulation can be presentas its pharmaceutically acceptable salt or salt-free form. As usedherein, “pharmaceutically acceptable salt” refers to derivatives of thedisclosed compounds wherein the active agent is modified by reacting itwith an acid or base as needed to form an ionically bound pair. Examplesof pharmaceutically acceptable salts include conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. Suitablenon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric,nitric and others known to those of ordinary skill in the art. The saltsprepared from organic acids such as amino acids, acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, and others areknown to those of ordinary skill in the art. The pharmaceuticallyacceptable salts of the present invention can be synthesized from theparent active agent which contains a basic or acidic moiety byconventional chemical methods. Lists of other suitable salts are foundin Remington's Pharmaceutical Sciences, 17^(th), ed., Mack PublishingCompany, Easton, Pa., 1985, the relevant disclosure of which is herebyincorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, the term “patient” or “subject” are taken to mean warmblooded animals such as mammals, for example, cats, dogs, mice, guineapigs, horses, bovine cows, sheep and humans.

A formulation of the invention can comprise an active agent present inan effective amount. By the term “effective amount”, is meant the amountor quantity of active agent that is sufficient to elicit the required ordesired response, or in other words, the amount that is sufficient toelicit an appreciable biological response when administered to asubject.

The formulation of the invention can be used to deliver one or moredifferent active agents. Particular combinations of active agents can beprovided by the present formulation. Some combinations of active agentsinclude: 1) a first drug from a first therapeutic class and a differentsecond drug from the same therapeutic class; 2) a first drug from afirst therapeutic class and a different second drug from a differenttherapeutic class; 3) a first drug having a first type of biologicalactivity and a different second drug having about the same biologicalactivity; 4) a first drug having a first type of biological activity anda different second drug having a different second type of biologicalactivity. Exemplary combinations of active agents are described herein.

When combinations of active agents are used, one or both of the activeagents can be present in a sub-therapeutic amount. As used herein, asub-therapeutic amount is that amount of first drug that provides lessthan a normal therapeutic response in patient to which the first drug isadministered in the absence of the second drug of the combination. Inother words, the first and second drugs may together provide anenhanced, improved, additive or synergistic therapeutic benefit ascompared to the administration of each drug alone, i.e., in the absenceof the other drug.

Following its preparation, the SAE-CD composition can be included in anyknown pharmaceutical formulation or dosage form. The compositions andformulations of the invention are suitable for administration to asubject by any means employed in the pharmaceutical industry. Exemplarymodes of administration include, without limitation, endobronchial(intrapulmonary, intratracheal, intraaveolar), oral, peroral, ocular,ophthalmic, otic, sublingual, buccal, transdermal, transmucosal, rectal,vaginal, uterine, urethral, intrathecal, nasal, parenteral,intraperitoneal, intramuscular, and subdermal administration.

A dosage form is available in a single or multiple dose form containingamong other things a quantity of active ingredient and the SAE-CDcomposition, said quantity being such that one or more predeterminedunits of the dosage form are normally required for a single therapeuticadministration. In the case of multiple dose forms, such as a scoredtablet, said predetermined unit will be one fraction such as a half orquarter of the multiple dose form. It will be understood that thespecific dose level for any patient will depend upon a variety offactors including the indication being treated, active agent employed,the activity of active agent, severity of the indication, patienthealth, age, sex, weight, diet, and pharmacological response, thespecific dosage form employed and other such factors.

Following preparation of the SAE-CD composition, it can be used toprepare a formulation wherein the SAE-CD composition is complexed withor not complexed with an active agent. By “complexed” is meant “beingpart of a clathrate or inclusion complex with”, i.e., a complexed activeagent is part of a clathrate or inclusion complex with a cyclodextrinderivative.

By active agent/CD complex is generally meant a clathrate or inclusioncomplex of a cyclodextrin derivative and an active agent. The ratio ofactive agent: CD present in the molecular complex can vary and can be inthe range of about 10 to about 0.1, on a molar basis. Thus, the CD willgenerally be, but need not be, present in excess of the active agent.The amount of excess will be determined by the intrinsic solubility ofthe agent, the expected dose of the agent, and the binding constant forinclusion complexation between the specific drug (agent) and thespecific CD derivative used. It should be noted that the cyclodextrinderivative can be present in uncomplexed form and therefore in amountssubstantially in excess of the amount of active agent present. Theweight ratio or molar ratio of derivatized cyclodextrin to active agentcan exceed 100, 1000 or even more.

Under some conditions, the SAE-CD composition can form one or more ionicbonds with a positively charged acid-ionizable compound. Therefore, itis possible for a compound to be complexed by way of an inclusioncomplex with the derivatized cyclodextrin and to be non-covalently butionically bound to the derivatized cyclodextrin.

Even though the SAE-CD composition can be the sole carrier or excipientin a formulation, it is possible to add other carriers to theformulation to further improve its performance.

The SAE-CD composition can be included in any formulation requiring aderivatized cyclodextrin. An active agent included in the formulationcan be delivered according to a rapid, immediate, pulsatile, timed,targeted, delayed and/or extended release formulation.

By “immediate release” is meant a release of an active agent to anenvironment over a period of seconds to no more than about 30 minutesonce release has begun and release begins within no more than about 2minutes after administration. An immediate release does not exhibit asignificant delay in the release of drug.

By “rapid release” is meant a release of an active agent to anenvironment over a period of 1-59 minutes or 0.1 minute to three hoursonce release has begun and release can begin within a few minutes afteradministration or after expiration of a delay period (lag time) afteradministration.

An extended release formulation containing the SAE-CD composition willrelease drug in an extended manner. Mechanisms employed for suchdelivery can include active agent release that is pH-dependent orpH-independent; diffusion or dissolution controlled; pseudo-zero order(approximates zero-order release), zero-order, pseudo-first order(approximates first-order release), or first-order, or rapid, slow,delayed, timed or sustained release or otherwise controlled release. Therelease profile for the active agent can also be sigmoidal in shape,wherein the release profile comprises an initial slow release rate,followed by a middle faster release rate and a final slow release rateof active agent. As used herein, the term “extended release” profileassumes the definition as widely recognized in the art of pharmaceuticalsciences. An extended release dosage form will release drug atsubstantially constant rate over an extended period of time or asubstantially constant amount of drug will be released incrementallyover an extended period of time. The term “extended release”, as regardsto drug release, includes the terms “controlled release”, “prolongedrelease”, “sustained release”, or “slow release”, as these terms areused in the pharmaceutical sciences. A controlled release can beginwithin a few minutes after administration or after expiration of a delayperiod (lag time) after administration. An extended release can beginwithin a few minutes after administration or after expiration of a delayperiod (lag time) after administration.

By “controlled release” is meant a release of an active agent to anenvironment over a period of about eight hours up to about 12 hours, 16hours, 18 hours, 20 hours, a day, or more than a day. By “sustainedrelease” is meant an extended release of an active agent to maintain aconstant drug level in the blood or target tissue of a subject to whichthe device is administered. A controlled release can begin within a fewminutes after administration or after expiration of a delay period (lagtime) after administration.

A timed release dosage form is one that begins to release drug after apredetermined period of time as measured from the moment of initialexposure to the environment of use.

A slow release dosage form is one that provides a slow rate of releaseof drug so that drug is released slowly and approximately continuouslyover a period of 3 hr, 6 hr, 12 hr, 18 hr, a day, 2 or more days, aweek, or 2 or more weeks, for example.

A targeted release dosage form generally refers to an oral dosage formthat designed to deliver drug to a particular portion of thegastrointestinal tract of a subject. An exemplary targeted dosage formis an enteric dosage form that delivers a drug into the middle to lowerintestinal tract but not into the stomach or mouth of the subject. Othertargeted dosage forms can delivery to other sections of thegastrointestinal tract such as the stomach, jejunum, ileum, duodenum,cecum, large intestine, small intestine, colon, or rectum.

A pulsatile release dosage form is one that provides pulses of highactive ingredient concentration, interspersed with low concentrationtroughs. A pulsatile profile containing two peaks may be described as“bimodal”.

A pseudo-first order release profile is one that approximates a firstorder release profile. A first order release profile characterizes therelease profile of a dosage form that releases a constant percentage ofan initial drug charge per unit time.

A pseudo-zero order release profile is one that approximates azero-order release profile. A zero-order release profile characterizesthe release profile of a dosage foml that releases a constant amount ofdrug per unit time.

Extended release formulations can be made according to the proceduresdescribed herein or in Biorelated Polymers and Gels: Controlled Releaseand Applications in Biomedical Engineering (ed. Teruo Okano; 1998);Encyclopedia of Controlled Drug Delivery (ed. Edith Mathiowitz; 1999);Future Strategies for Drug Delivery with Particulate Systems (ed. J. E.Diederichs; 1998); Controlled Release Series (ed. J. M. Anderson; 1987);Controlled Drug Delivery Series (Ed. S. D. Bruck; 1983); ControlledRelease of Drugs Series (ed. M. Rosoff; 1989); Controlled ReleaseTechnology: Pharmaceutical Applications (ACS Symposium Series No. 348)(eds. P. I. Lee and W. R. Good; 1987); Extended Release Dosage Forms(ed. L. Krowczynski; 1987); Handbook of Pharmaceutical ControlledRelease Technology (ed. D. L. Wise; 2000); Intelligent Materials forControlled Release (ed. S. M. Dinh; 1999); Multicomponent Transport inPolymer Systems for Controlled Release (Polymer Science and EngineeringMonograph Series) (ed. A. Polishchuk; 1997); Pharmaceutical Technology:Controlled Drug Release (ed. M. Rubenstein; 1987); Polymers forControlled Drug Delivery (ed. P. J. Tarcha; 1991); Tailored PolymericMaterials for Controlled Delivery Systems (ACS Symposium Series No. 709)(ed. I. McCulloch; 1998); Oral Colon-Specific Drug Delivery (ed. D. R.Friend, 1992); and other publications known to those of ordinary skillin the art, the entire disclosures of which are hereby incorporated byreference.

The extended release layer can be a matrix diffusion, erosion,dissolution, or disintegration-controlled composition comprising a drugand one or more release rate modifying excipients and other optionalexcipients.

By “delayed release” is meant that initial release of drug from arespective drug-containing layer occurs after expiration of anapproximate delay (or lag) period. For example, if release of drug fromthe extended release layer is delayed two hours, then release of drugfrom that layer begins at about two hours after administration of themulti-layered tablet to a subject. In general, a delayed release isopposite an immediate release, wherein release of drug begins after nomore than a few minutes after administration. Accordingly, the drugrelease profile from a particular layer can be a delayed-extendedrelease or a delayed-rapid release. A “delayed-extended” release profileis one wherein extended release of drug begins after expiration of aninitial delay period. A “delayed-rapid”release profile is one whereinrapid release of drug begins after expiration of an initial delayperiod.

Although not necessary, a formulation of the present invention caninclude antioxidants, acidifying agents, alkalizing agents, bufferingagents, solubility-enhancing agents, penetration enhancers,electrolytes, fragrances, glucoses, glidants, stabilizers, bulkingagents, cryoprotectants, plasticizers, flavors, sweeteners, surfacetension modifiers, density modifiers, volatility modifiers, hydrophilicpolymers, preservatives, antibacterial agents, colorants, antifungalagents, complexation enhancing agents, solvents, salt, water, tonicitymodifiers, antifoaming agents, oil, penetration enhancers, otherexcipients known by those of ordinary skill in the art for use inpharmaceutical formulations, or a combination thereof. Upon eachoccurrence, these materials can be independently included in the activeagent-containing particles or the carrier particles. For example, thecarrier might include one or more of these materials and the activeagent-containing particles might also include one or more of thesematerials.

As used herein, the term “glidant” is intended to mean an agent used topromote flowability of the dry powder. Such compounds include, by way ofexample and without limitation, magnesium stearate, sodiumdodecylsulfate, colloidal silica, cornstarch, talc, calcium silicate,magnesium silicate, colloidal silicon, silicon hydrogel and othermaterials known to one of ordinary skill in the art.

As used herein, the term “antioxidant” is intended to mean an agent thatinhibits oxidation and thus is used to prevent the deterioration ofpreparations by the oxidative process. Such compounds include, by way ofexample and without limitation, acetone, potassium metabisulfite,potassium sulfite, ascorbic acid, ascorbyl palmitate, citric acid,butylated hydroxyanisole, butylated hydroxytoluene, hypophophorous acid,monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate,sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehydesulfoxylate, thioglycolic acid, EDTA, pentetate, and sodiummetabisulfite and others known to those of ordinary skill in the art.

As used herein, the term “alkalizing agent” is intended to mean acompound used to provide alkaline medium when the dry powder of theinvention is exposed to water. Such compounds include, by way of exampleand without limitation, ammonia solution, ammonium carbonate,diethanolamine, monoethanolamine, potassium hydroxide, sodium borate,sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine,diethanolamine, organic amine base, alkaline amino acids and trolamineand others known to those of ordinary skill in the art.

As used herein, the term “acidifying agent” is intended to mean acompound used to provide an acidic medium when the dry powder of theinvention is exposed to water. Such compounds include, by way of exampleand without limitation, acetic acid, acidic amino acids, citric acid,fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbicacid, phosphoric acid, sulfuric acid, tartaric acid and nitric acid andothers known to those of ordinary skill in the art.

As used herein, the term “buffering agent” is intended to mean acompound used to resist change in pH upon exposure to a medium of adifferent pH. Buffers are used in the present compositions to adjust thepH to a range of between about 2 and about 8, about 3 to about 7, orabout 4 to about 5. By controlling the pH of the dry powder, irritationto the respiratory tract can be minimized. Such compounds include, byway of example and without limitation, acetic acid, sodium acetate,adipic acid, benzoic acid, sodium benzoate, boric acid, sodium borate,citric acid, glycine, maleic acid, monobasic sodium phosphate, dibasicsodium phosphate, HEPES, lactic acid, tartaric acid, potassiummetaphosphate, potassium phosphate, monobasic sodium acetate, sodiumbicarbonate, tris, sodium tartrate and sodium citrate anhydrous anddihydrate and others known to those of ordinary skill in the art. Otherbuffers include citric acid/phosphate mixture, acetate, barbital,borate, Britton-Robinson, cacodylate, citrate, collidine, formate,maleate, Mcllvaine, phosphate, Prideaux-Ward, succinate,citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES(2-(N-morpholino)ethanesulfonic acid), BIS-TRIS(bis(2-hydroxyethyl)imino-tris(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS(3-(N-morpholino)propanesulfonic acid). TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS(4-(N-morpholino)-butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid),TRIZMA™ (tris(hydroxymethylaminomethane), HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid), POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA(triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propanesulfonic acid), TRICINE(N-tris(hydroxymethyl)-methylglycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS(N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), AMPD(2-amino-2-methyl-1,3-propanediol), and/or any other buffers known tothose of skill in the art.

A complexation-enhancing agent is a compound, or compounds, thatenhance(s) the complexation of an active agent with the derivatizedcyclodextrin. When the complexation-enhancing agent is present, therequired ratio of derivatized cyclodextrin to active agent may need tobe changed such that less derivatized cyclodextrin is required. Suitablecomplexation enhancing agents include one or more pharmacologicallyinert water soluble polymers, hydroxy acids, and other organic compoundstypically used in liquid formulations to enhance the complexation of aparticular agent with cyclodextrins. Suitable water soluble polymersinclude water soluble natural polymers, water soluble semisyntheticpolymers (such as the water soluble derivatives of cellulose) and watersoluble synthetic polymers. The natural polymers include polysaccharidessuch as inulin, pectins, algin derivatives and agar, and polypeptidessuch as casein and gelatin. The semi-synthetic polymers includecellulose derivatives such as methylcellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, their mixed ethers such as hydroxypropylmethylcellulose and other mixed ethers such as hydroxyethylethylcellulose, hydroxypropyl ethylcellulose, hydroxypropylmethylcellulose phthalate and carboxymethylcellulose and its salts,especially sodium carboxymethylcellulose. The synthetic polymers includepolyoxyethylene derivatives (polyethylene glycols) and polyvinylderivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrenesulfonate) and various copolymers of acrylic acid (e.g. carbomer).Suitable hydroxy acids include by way of example, and withoutlimitation, citric acid, malic acid, lactic acid, and tartaric acid andothers known to those of ordinary skill in the art.

As used herein, the term “preservative” is intended to mean a compoundused to prevent the growth of microorganisms. Such compounds include, byway of example and without limitation, benzalkonium chloride,benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridiniumchloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuricnitrate, phenylmercuric acetate, thimerosal, metacresol, myristylgammapicolinium chloride, potassium benzoate, potassium sorbate, sodiumbenzoate, sodium propionate, sorbic acid, thymol, and methyl, ethyl,propyl, or butyl parabens and others known to those of ordinary skill inthe art.

As used herein, the term “colorant” is intended to mean a compound usedto impart color to pharmaceutical preparations. Such compounds include,by way of example and without limitation, FD&C Red No. 3, FD&C Red No.20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No.5, D&C Red No. 8, caramel, and iron oxide (black, red, yellow), otherF.D. & C, dyes and natural coloring agents such as grape skin extract,beet red powder, beta-carotene, annato, carmine, turmeric, paprika,combinations thereof and other such materials known to those of ordinaryskill in the art.

As used herein, the term “tonicity modifier” is intended to mean acompound or compounds that can be used to adjust the tonicity of theliquid formulation. Suitable tonicity modifiers include glycerin,lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol,trehalose and others known to those or ordinary skill in the art.

As used herein, the term “antifoaming agent” is intended to mean acompound or compounds that prevents or reduces the amount of foamingthat forms on the surface of the fill composition. Suitable antifoamingagents include by way of example and without limitation, dimethicone,simethicone, octoxynol and others known to those of ordinary skill inthe art.

Hydrophilic polymers can be used to improve the performance offormulations containing a cyclodextrin. Loftsson (U.S. Pat. Nos.5,324,718 and 5,472,954) has disclosed a number of polymers suitable forcombined use with a cyclodextrin (underivatized or derivatized) toenhance the performance and/or properties of the cyclodextrin. Suitablepolymers are disclosed in Pharmazie (2001), 56(9), 746-747;International Journal of Pharmaceutics (2001), 212(1), 29-40;Cyclodextrin: From Basic Research to Market, International CyclodextrinSymposium, 10th, Ann Arbor, Mich. United States, May 21-24, 2000 (2000),10-15 (Wacker Biochem Corp.; Adrian, Mich.); PCT InternationalPublication No. WO 9942111; Pharmazie, 53(11), 733-740 (1998); Pharm.Technol. Eur., 9(5), 26-34 (1997); J. Pharm. Sci. 85(10), 1017-1025(1996); European Patent Application EP0579435; Proceedings of theInternational Symposium on Cyclodextrins, 9th, Santiago de Comostela,Spain, May 31-Jun. 3, 1998 (1999), 261-264 (Editor(s): Labandeira, J. J.Torres; Vila-Jato, J. L. Kluwer Academic Publishers, Dordrecht, Neth);S.T.P. Pharma Sciences (1999), 9(3), 237-242; ACS Symposium Series(1999), 737 (Polysaccharide Applications), 24-45; PharmaceuticalResearch (1998), 15(11), 1696-1701; Drug Development and IndustrialPharmacy (1998), 24(4), 365-370; International Journal of Pharmaceutics(1998), 163(1-2), 115-121; Book of Abstracts, 216th ACS NationalMeeting, Boston, Aug. 23-27 (1998), CELL-016, American Chemical Society;Journal of Controlled Release, (1997), 44/1 (95-99); Pharm. Res. (1997)14(11), S203; Investigative Ophthalmology & Visual Science, (1996),37(6), 1199-1203; Proceedings of the International Symposium onControlled Release of Bioactive Materials (1996), 23rd, 453-454; DrugDevelopment and Industrial Pharmacy (1996), 22(5), 401-405; Proceedingsof the International Symposium on Cyclodextrins, 8th, Budapest, Mar.31-Apr. 2, (1996), 373-376. (Editor(s): Szejtli, J.; Szente, L. Kluwer:Dordrecht, Neth.); Pharmaceutical Sciences (1996), 2(6), 277-279;European Journal of Pharmaceutical Sciences, (1996) 4(SUPPL.). S144;Third European Congress of Pharmaceutical Sciences Edinburgh, Scotland.UK Sep. 15-17, 1996; Pharmazie, (1996), 51(1), 39-42; Eur. J. Pharm.Sci. (1996), 4(Suppl.), S143; U.S. Pat. Nos. 5,472,954 and 5,324,718;International Journal of Pharmaceutics (Netherlands), (Dec. 29, 1995)126, 73-78; Abstracts of Papers of the American Chemical Society, (2Apr. 1995) 209(1), 33-CELL; European Journal of Pharmaceutical Sciences,(1994) 2, 297-301; Pharmaceutical Research (New York), (1994) 11(10),S225; International Journal of Pharmaceutics (Netherlands). (Apr. 11,1994) 104, 181-184; and International Journal of Pharmaceutics (1994),110(2), 169-77, the entire disclosures of which are hereby incorporatedby reference.

Other suitable polymers are well-known excipients commonly used in thefield of pharmaceutical formulations and are included in, for example,Remington's Pharmaceutical Sciences, 18th Edition, Alfonso R. Gennaro(editor), Mack Publishing Company, Easton, Pa., 1990, pp. 291-294;Alfred Martin, James Swarbrick and Arthur Commarata, Physical Pharmacy,Physical Chemical Principles in Pharmaceutical Sciences, 3rd edition(Lea & Febinger, Philadelphia, Pa., 1983, pp. 592-638); A. T. Florenceand D. Altwood, (Physicochemical Principles of Pharmacy, 2nd Edition,MacMillan Press. London, 1988, pp. 281-334. The entire disclosures ofthe references cited herein are hereby incorporated by references. Stillother suitable polymers include water-soluble natural polymers,water-soluble semi-synthetic polymers (such as the water-solublederivatives of cellulose) and water-soluble synthetic polymers. Thenatural polymers include polysaccharides such as inulin, pectin, alginderivatives (e.g. sodium alginate) and agar, and polypeptides such ascasein and gelatin. The semi-synthetic polymers include cellulosederivatives such as methylcellulose, hydroxyethylcellulose,hydroxypropyl cellulose, their mixed ethers such as hydroxypropylmethylcellulose and other mixed ethers such as hydroxyethylethylcellulose and hydroxypropyl ethylcellulose, hydroxypropylmethylcellulose phthalate and carboxymethylcellulose and its salts,especially sodium carboxymethylcellulose. The synthetic polymers includepolyoxyethylene derivatives (polyethylene glycols) and polyvinylderivatives (polyvinyl alcohol, polyvinylpyrrolidone and polystyrenesulfonate) and various copolymers of acrylic acid (e.g. carbomer). Othernatural, semi-synthetic and synthetic polymers not named here which meetthe criteria of water solubility, pharmaceutical acceptability andpharmacological inactivity are likewise considered to be within theambit of the present invention.

A solubility-enhancing agent can be added to a formulation of theinvention. A solubility-enhancing agent is a compound, or compounds,that enhance(s) the solubility of active agent in an aqueous or moistenvironment, such as the lining of respiratory tract. Suitablesolubility enhancing agents include one or more organic solvents,detergents, soaps, surfactants and other organic compounds typicallyused in parenteral formulations to enhance the solubility of aparticular agent. Suitable organic solvents include, for example,ethanol, glycerin, poly(ethylene glycols), propylene glycol,poly(propylene glycols), poloxamers, and others known to those ofordinary skill in the art.

As used herein, the term “cryoprotectant” is intended to mean a compoundused to protect an active agent from physical or chemical degradationduring lyophilization. Such compounds include, by way of example andwithout limitation, dimethyl sulfoxide, glycerol, trehalose, propyleneglycol, polyethylene glycol, and others known to those of ordinary skillin the art.

Plasticizers can also be included in the preparations of the inventionto modify the properties and characteristics thereof. As used herein,the term “plasticizer” includes all compounds capable of plasticizing orsoftening a polymer or binder used in invention. The plasticizer shouldbe able to lower the melting temperature or glass transition temperature(softening point temperature) of the polymer or binder. Plasticizers,such as low molecular weight PEG, generally broaden the averagemolecular weight of a polymer in which they are included therebylowering its glass transition temperature or softening point.Plasticizers also generally reduce the viscosity of a polymer. It ispossible the plasticizer will impart some particularly advantageousphysical properties to the osmotic device of the invention.

Plasticizers useful in the invention can include, by way of example andwithout limitation, low molecular weight polymers, oligomers,copolymers, oils, small organic molecules, low molecular weight polyolshaving aliphatic hydroxyls, ester-type plasticizers, glycol ethers,poly(propylene glycol), multi-block polymers, single block polymers, lowmolecular weight poly(ethylene glycol), citrate ester-type plasticizers,triacetin, propylene glycol and glycerin. Such plasticizers can alsoinclude ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol,styrene glycol, diethylene glycol, triethylene glycol, tetraethyleneglycol and other poly(ethylene glycol) compounds, monopropylene glycolmonoisopropyl ether, propylene glycol monoethyl ether, ethylene glycolmonoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate,ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate,acetyltributylcitrate, triethyl citrate, acetyl triethyl citrate,tributyl citrate and allyl glycolate. All such plasticizers arecommercially available from sources such as Aldrich or Sigma ChemicalCo. It is also contemplated and within the scope of the invention, thata combination of plasticizers may be used in a formulation of theinvention. The PEG based plasticizers are available commercially or canbe made by a variety of methods, such as disclosed in Poly(ethyleneglycol) Chemistry: Biotechnical and Biomedical Applications (J. M.Harris, Ed.; Plenum Press, N.Y.) the disclosure of which is herebyincorporated by reference.

As used herein, the term “flavor” is intended to mean a compound used toimpart a pleasant flavor and often odor to a pharmaceutical preparation.Exemplary flavoring agents or flavorants include synthetic flavor oilsand flavoring aromatics and/or natural oils, extracts from plants,leaves, flowers, fruits and so forth and combinations thereof. These mayalso include cinnamon oil, oil of wintergreen, peppermint oils, cloveoil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil ofnutmeg, oil of sage, oil of bitter almonds and cassia oil. Other usefulflavors include vanilla, citrus oil, including lemon, orange, grape,lime and grapefruit, and fruit essences, including apple, pear, peach,strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.Flavors which have been found to be particularly useful includecommercially available orange, grape, cherry and bubble gum flavors andmixtures thereof. The amount of flavoring may depend on a number offactors, including the organoleptic effect desired. Flavors will bepresent in any amount as desired by those of ordinary skill in the art.Particularly flavors are the grape and cherry flavors and citrus flavorssuch as orange.

As used herein, the term “sweetener” is intended to mean a compound usedto impart sweetness to a preparation. Such compounds include, by way ofexample and without limitation, aspartame, dextrose, glycerin, mannitol,saccharin sodium, sorbitol, fructose, high fructose corn syrup,maltodextrin, sucralose, sucrose, other materials known to one ofordinary skill in the art, and combinations thereof.

As used herein, a penetration enhancer is an agent or combination ofagents that enhances penetration of an active agent through tissue.Penetration enhancers which can be included in a formulation of theinvention include, by way of example and without limitation, calciumchelators such as EDTA, methylated P-cyclodextrin, and polycarboxylicacids; surfactants such as sodium lauryl sulfate, sodium dodecylsulfate, carnitine, carnitine esters, and tween; bile salts such assodium taurocholate; fatty acids such as oleic and linoleic acid; andnon-surfactants such as AZONE™ and dialkyl sulfoxides; E-flux inhibitorssuch as AV171 (AyMax, Inc., South San Francisco, Calif.), D-α-tocopherylpolyethylene glycol 1000 succinate (TPGS), and peppermint oil; chitosanand chitosan derivatives such as N-methyl chitosan, N-trimethylchitosan, mono-N-carboxymethyl chitosan, quaternized chitosanderivatives; SNAC (N-(8-(2-hydroxybenzoyl) amino) caprylate) and SNAD(N-(10-(2-hydroxybenzoyl)amino)-decanoate) (Emisphere Technologies.Inc., Tarrytown, N.Y.); N-acylated non-alpha amino acids; HEMISPHEREbrand delivery agents; Gélucire 44/14 or Vitamin E TPGS; CARBOPOL® 934P;others known to those of ordinary skill in the art; and combinationsthereof.

As used herein, a fragrance is a relatively volatile substance orcombination of substances that produces a detectable aroma, odor orscent. Exemplary fragrances include those generally accepted as FD&C.

A “surface tension modifier” is a material or combination of materialscapable of modifying the surface properties of a composition accordingto the invention. A surface tension modifier can include a surfactant,detergent or soap. It can be included in the carrier particles, theactive agent-containing particles or both.

A “density modifier” is a material or combination of materials that isincluded in a composition of the invention to increase or decrease thedensity thereof. It can be included in the carrier particles, the activeagent-containing particles or both. A density modifier can be used toincrease or decrease (as needed) the density of the carrier in orderenhance dispersion of the active agent from the carrier. Likewise, adensity modifier can be used to decrease or increase, respectively, (asneeded) the density of the active agent containing particles.

A “volatility modifier” is a material or combination of materials addedto modify the volatility of an active agent. In one embodiment, thevolatility modifier increases the volatility of the active agent. Inanother, embodiment, the volatility modifier decreases the volatility ofthe active agent.

As used herein, the term “stabilizer” is intended to mean a compoundused to stabilize the therapeutic agent against physical, chemical, orbiochemical process that would reduce the therapeutic activity of theagent. Suitable stabilizers include, by way of example and withoutlimitation, albumin, sialic acid, creatinine, glycine and other aminoacids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose,glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycols,sodium caprylate and sodium saccharin and other known to those ofordinary skill in the art.

As used herein, the term “bulking agent” is intended to mean a compoundused to add bulk to the lyophilized product and/or assist in the controlof the properties of a formulation during lyophilization. Such compoundsinclude, by way of example and without limitation, dextran, trehalose,sucrose, polyvinylpyrrolidone, lactose, inositol, sorbitol,dimethylsulfoxide, glycerol, albumin, calcium lactobionate, and othersknown to those of ordinary skill in the art.

It should be understood that compounds used in the art of pharmaceuticalformulations generally serve a variety of functions or purposes. Thus,if a compound named herein is mentioned only once or is used to definemore than one term herein, its purpose or function should not beconstrued as being limited solely to that named purpose(s) orfunction(s).

In view of the above description and the examples below, one of ordinaryskill in the art will be able to practice the invention as claimedwithout undue experimentation. The foregoing will be better understoodwith reference to the following examples that detail certain proceduresfor the preparation of compositions and formulations according to thepresent invention. All references made to these examples are for thepurposes of illustration. The following examples should not beconsidered exhaustive, but merely illustrative of only a few of the manyembodiments contemplated by the present invention.

Example 1

Exemplary formulations were made according to the following generalprocedures.

Method A. Solid Formulation in Admixture

A solid composition comprising cyclodextrin is mixed with a solidcomposition comprising active agent until homogeneity. Thecyclodextrin-containing and active agent-containing compositions containless than about 20% wt. water. Mixing of the two compositions can alsoinclude simultaneous attritting thereof or attrition can be performed asa separate process step. For example, the cyclodextrin-containingcomposition and the active agent-containing compositions are eachattritted separately prior to mixing. One or more additional excipientscan be included in the SAE-CD composition and/or the active agentcomposition.

Method B. Liquid Formulation

An SAE-CD composition is mixed with a liquid carrier optionallycontaining an active agent. The SAE-CD composition can be mixed with theliquid carrier either prior to, after or during addition of the activeagent, if one is present. One or more other excipients can be includedin the formulation. If needed, heat can be applied to promote mixing ordissolution.

Example 2

Preparation of SAE-CD Solid Compositions.

In Methods A and B below, the SAE-CD starting material was provided inan aqueous liquid carrier, and the SAE-CD starting material was preparedaccording to a known literature method. Particular embodiments includedSAE-CD starting material dissolved in water. The concentration of SAE-CDin the liquid carrier was varied as needed to provide a liquid feed ofthe desired viscosity or solids content.

Method A. Fluidized Bed Spray Drying

An SAE-CD carrier was prepared by spray agglomeration in an FSD-16 fluidspray drier apparatus (GEA Niro Inc., Columbia Md.) as follows. Severalsolutions of sulfobutyl ether-beta-cyclodextrin (degree ofsubstitution-7, SBE7-BCD) at 20.1-49.8% solids were agglomerated in theFSD-16 using a top mounted Spraying Systems pressure nozzle atatomization pressures of 1,500-2,000 psig and feed temperature ˜25° C.Process conditions were inlet/outlet temperatures of 210-250/83-100° C.,fluid bed inlet temperatures of 80-100° C., and fluid product bedtemperatures of 67-87° C. Fines return at the atomizer nozzle and at thechamber cone was investigated during separate runs. The drying gas flowsare heated electrically.

Feed solutions containing SAE-CD were prepared by adding powderedconstituents to the required amount of water under heat and agitation inthe feed tank.

Method B. Fluidized Bed Spray Drying

An SAE-CD composition was prepared by spray agglomeration in an FSD-12.5fluid spray drier apparatus (GEA Niro Inc., Columbia Md.) with attached3-chamber fluidization bed. The inner fluid bed chamber (chamber 1) wasdirectly open to the drying chamber and was used for finalagglomeration, drying of agglomerates and dedusting. The outer ringfluid bed chambers 2 and 3 are connected sequentially to chamber 1 suchthat product moves from chamber 1 to chamber 2 to chamber 3 ascontrolled by process conditions. Chamber 2 was used for post drying andcontinued dedusting. Chamber 3 was used for cooling and final dedusting.The final product was taken from chamber 3. The drying gas (N₂) flowsare heated electrically and the main drying gas was introduced into thedrying chamber through a ceiling air disperser. The drying gas to thethree fluid bed chambers was evenly distributed across perforatedplates. The drying gas flows were individually adjusted to the differentfluid bed chambers.

Solutions of sulfobutyl ether-beta-cyclodextrin (degree ofsubstitution-7. SBE7-BCD) at 48-52% wt solids were agglomerated in theFSD-12.5 using a top-mounted Spraying Systems pressure nozzle atatomization pressures of 10-50 bar and a solution temperature of 45-55°C. Process conditions were inlet/outlet temperatures of 150-170/70-90°C. chamber 1 fluid bed inlet temperatures of 100-150° C., and chamber 1product bed temperatures of 60-100° C. Fines were returned at a locationadjacent the atomizer nozzle.

Example 3

The particle diameter (size) distribution of several SAE-CD compositions(sulfobutyl ether-beta-cyclodextrin, degree of substitution ˜7) wasdetermined by laser diffraction (Malvern Instruments Inc, Model 2000,South Borough, Mass.), equipped with a dry powder feeder attachment. Thedispersion pressure versus particle size curve was generated and basedupon a dispersion pressure of 60 psi. The powder was sampled using 500detector sweeps for statistical validity. The obscuration values weremonitored to ensure adequate data acquisition. The 300 mm focal lengthdetector lens was used, providing a size range of 5.8 to 564μ.

The particle size analysis data for exemplary SAE-CD compositions ofsulfobutyl ether-beta-cyclodextrin with an average degree ofsubstitution of ˜7, SBE7-BCD, is included in the table below. The datafor each composition indicate the particle diameters in micronscorresponding to the De Brouckere mean diameter (D[4.3]) or the particlesize cutoffs for the 10%, 50% or 90% cumulative volume fractions. (μ istaken to mean micron.)

Particle Size Cutoff at the Stated Mean Diameter Volume DistributionPercentiles (D[4,3]) 10% 50% 90% SAE-CD Lot Size (μ) D[v, 0.1] D[v, 0.5]D[v, 0.9] *B3 78.7 28.7 67.9 138.1 B4 86.9 30.2 79.1 154.1 B5 83.8 33.176.7 145.4 B9 104.9 34.9 96.5 184.9 **A1 175 A2 194 A3 119 A4 125 A5 92A6 187 A7 164 *“B#” denotes a SAE-CD composition made according toExample 2, Method B, wherein “#” indicates the lot number of the sample.**“A#” denotes a SAE-CD composition made according to Example 2, MethodA, wherein “#” indicates the lot number of the sample.

Example 4

The moisture content of the SAE-CD compositions was measured via theKarl Fisher method (USP<921>, Method Ia) or the moisture balance method.

Moisture Balance Method

Computrac Model 200 XL moisture balance (Arizona Instruments, Tempe,Ariz.) was used to determine the weight loss of selected powder samplesover time as the powder was exposed to infrared heating. The powderswere weighed (approximately 1 g for each sample), heated at 110° C.until no change in weight was observed, and the percentage weight losscalculated.

Example 5

The flowability of solid SAE-CD compositions was determined with a testapparatus (Flodex™, Hanson Research Corp., Northridge, Calif.) having:

-   -   A stainless steel cylinder with an approximate capacity of 200        mL    -   A series of stainless steel disks. Each disk having a precise        hole in the center in graduated sizes differing 1-2 mm in        diameter that is easily attached to form a bottom for the        cylinder.    -   A shutter that covers the hole and that may be quickly removed        without vibration to allow the powder to flow through the        selected hole.    -   An adjustable funnel for loading the sample cylinder with a free        fall of the test powder.    -   A suitable container to collect the powder that flows through        the unit.

The funnel was mounted above the cylinder such that the bottom of thefunnel was near but not touching the powder surface once loaded into thecylinder. A disk was inserted into the bottom of the cylinder and thehole in the disk was closed. A powder load of 50 g was then pouredthrough the funnel into the middle of the cylinder. The powder wasallowed to set in the cylinder for at least 30 seconds, then the hole inthe disk was opened quickly and without vibration. The flow through thedisk opening was then observed. A positive result was when the powderflowed through the hole leaving a cavity shaped like an upside-down,truncated cone in 3 of 3 trials and the powder that falls involves theentire height of the powder (not less than 60 mm).

A negative result was noted when the powder fell abruptly through thehole forming a cylindrical cavity in the remaining powder.

If the result was positive, the procedure was repeated with disks havingsmaller diameter holes until the smallest diameter hole still giving apositive result in 3 of 3 trials was determined.

If the result was negative, the procedure was repeated with disks havinglarger diameter holes until the smallest diameter hole giving a positiveresult in 3 of 3 trials was determined.

Results of the measurements for SAE-CD compositions (sulfobutylether-beta-cyclodextrin with a degree of substitution of ˜7, SBE7-B-CD)are given below.

SBE7-B- Minimum orifice diameter CD lot (mm) B4 6 B9 6 A1 9 A2 8 A3 5 A44 A5 10 A6 12 A7 10

Example 6

The average dissolution time of SAE-CD compositions (sulfobutylether-beta-cyclodextrin with an average degree of substitution ˜7,SBE7-BCD) was determined by a flow-through dissolution device comprisinga glass filter holder (Millipore Corp., Billerica, Mass.) attached to apump and water reservoir. The filter holder was comprised of a ˜300 mLcapacity funnel and a fritted glass base held together with a metalclamp.

The test was conducted by placing a 2.5 g sample of the powder onto a 47mm×10 micron pore size filter mounted between the sections of the filterholder. Water at ˜25° C. was pumped at a rate of 100 mL per minutethrough the bottom of the apparatus such that the water would risethrough the filter and into the reservoir. The sample was observed todetermine the time required for dissolution of all the solids. If thesample floated and required longer than 2.5 minutes to dissolve, thepump was stopped after delivering 250 mL.

Representative data for sulfobutyl lether-beta-cyclodextrin with anaverage degree of substitution of 7 (SBE₇-CD) are included in the tablebelow.

SBE₇-CD Dissolution Time (minutes) Composition Run 1 Run 2 Average B33.0 3.5 3.25 B4 2.0 2.25 2.13 B5 2.0 2.0 2.0 B6 2.5 2.5 2.5 B8 2.0 2.52.25 B10 2.25 2.0 2.13 A5 2.0 2.0 2.0

Example 7

SAE-CD compositions were compared in compaction studies to samples ofcommercial powders often used in preparing tablets, e.g.microcrystalline cellulose (Avicel 200), lactose USP, and dibasiccalcium phosphate dihydrate (DiCal).

The powders were compressed on an instrumented Colton single stationpress, running at 15 tablets per minute. The press had an instrumentedupper and lower punch compression force and displacement. The sampleweight was 200 mg and the samples were compressed to three differenttablet hardnesses of approximately 5, 10 and 15 kP using flat-facedpunches with a diameter of 0.345 inches. The force and displacement datawere collected using a 4-channel, 12-bit digital oscilloscope (Model#420, Nicolet Instrument Corp., Madison, Wis., USA); samples werecollected every msec simultaneously for each of the four channels. Thedie was lubricated with a 10% (w/v) slurry of magnesium stearate inacetone applied with a cotton swab. To maintain tablet-to-tabletconsistency, a standardized procedure was developed for swabbing anddrying the slurry onto the die wall. The die-wall coverage was alsochecked by visual inspection. To reduce signal noise, Fast Fouriertransform (FFT) was performed on the upper and lower punch data usingIgor Pro version 3.1 (Wavemetrics, Inc., Oregon). The Igor Pro was alsoused to find the Pmax in the average tablet pressure curve (i.e.,maximum punch pressure) after the FFT had been performed; the softwarealgorithm found the minimum using the derivative of the curve.

Tablet breaking strength was measured with a KEY® HT-300 hardness tester(Englishtown, N.J.). A dial indicator was used to measure postcompression tablet height. Typically, 5 tablets were compressed andtested for hardness at each of the three target hardness levels.

Example 8

The density and compressibility of SAE-CD compositions was determined bythe following methods:

Method A. Bulk Density

Bulk density of SAE-CD compositions was determined according to USP<616> Method I, using a 100 mL graduated cylinder.

Method B. Tapped Density

Tapped density of SAE-CD compositions was determined by USP <616> MethodI, using a 100 mL graduated cylinder.

Method C. Carr's Compressibility Index

The Carr's compressibility index of SAE-CD compositions was calculatedaccording to the formula:

${\%\mspace{14mu}{compressibility}} = {\left( \frac{{{Tap}\mspace{14mu}{Density}} - {{Bulk}\mspace{14mu}{Density}}}{{Tap}\mspace{14mu}{Density}} \right) \times 100\%}$

Method D. True Density

The true density of SAE-CD compositions was determined with aMultivolume Pycnometer (Micromeritics Instrument Corp., Model 1305,Norcross, Ga.) according to the USP <699> method. A sample holder havinga one cm³ volume was used for all measurements.

The results of the measurements for SAE-CD compositions (sulfobutylether-beta-cyclodextrin with and average degree of substitution-7,SBE7-BCD, are given in the table below.

SBE7-BCD Bulk Density Tapped Density Carr's Index True Density Sample(g/cm³) (g/cm³) (%) (g/cm³) B3 0.610 0.731 16.6 1.29 B4 0.594 0.701 15.31.30 B5 0.601 0.708 15.1 1.30 B6 0.604 0.692 12.8 B8 0.573 0.670 14.6 B91.28 B10 0.595 0.694 14.2 A1 0.429 0.564 23.9 A2 0.410 0.539 23.9 A30.549 0.670 18.1 A4 0.549 0.661 16.9 A5 0.481 0.574 16.0 A6 0.433 0.52818.0 A7 0.381 0.495 23.0

Example 9

A dry powder formulation suitable for administration with a DPI devicecomprises one or more active agents, SAE-CD composition carrier andoptionally one or more excipients selected from the group consisting ofan antioxidant, acidifying agent, alkalizing agent, buffering agent,solubility-enhancing agent, penetration enhancer, electrolyte,fragrance, glucose, glidant, stabilizer, bulking agent, cryoprotectant,plasticizer, flavors, sweeteners, surface tension modifier, densitymodifier, volatility modifier, or a combination thereof. The SAE-CDcarrier comprises about 50%-99.9% wt. of the formulation, and it has amedian particle diameter of less than 420 microns. The activeagent-containing particles have a median particle diameter between about0.1 to 10 microns. The carrier has a span of about 1.5 to 2.9, and thecarrier has been made according to invention, and optionally attrittingthe solid to form the particulate carrier. The SAE-CD used in thecarrier has an average DS in the range of about 1 to 12.

Example 10

A compressed rapid release tablet comprising sulfobutylether-beta-cyclodextrin with an average degree of substitution of 4(SBE₄-BCD, SAE-CD composition), and piroxicam is prepared according tothe following formula and procedure.

Ingredient Amount (mg) 1: Piroxicam 10 1: SBE₄-βCD 77 2: sorbitol 45 2:dextrose 50 2: citric acid 10 2: xylitol 47.5 2: PEG 3350 9 3: magnesiumstearate 1.5 3: fumed silicon dioxide 1.5 3: croscarmellose sodium 5.5Total 257

The above ingredients are used to make a 257 mg tablet core having arapid release profile. The numbers beside the ingredients indicates thegeneral order of addition. After each group of ingredients is added, themixture is dry blended for 5-10 min. The magnesium stearate, fumedsilicon dioxide (CABOSIL™ M5P) and croscarmellose sodium are added inseparately (step 3) from other ingredients and an additional 5 min. dryblend step is added to the general procedure.

The powder is then compressed to form a tablet with a hardness of about8-10 Kg.

Example 11

A controlled release tablet comprising an SAE-CD composition, sulfobutylether-beta-cyclodextrin with an average degree of substitution of 7(SBE₇-PCD), and prednisolone is prepared according to the followingformula and procedure.

Ingredient Amount (mg) Prednisolone 15 SBE₇-βCD 210 Hydroxypropylmethylcellulose 75 (HPMC K100M) Total 300

The above ingredients are used to make a 300 mg tablet core having acontrolled release profile. The ingredients are blended by hand andindividual tablets are prepared on a carver press under a pressure of 1ton for 7 seconds. The tablets are prepared using a 5/16″ standard cupconcave tooling.

Example 12

An orodispersable immediate release tablet comprising an SAE-CDcomposition, sulfobutyl ether-gamma-cyclodextrin with an average degreeof substitution of 7 (SBE₇-γCD), and zaleplon is prepared according tothe following formula and procedure.

Ingredient Amount per tablet (mg) Zaleplon 5 Croscarmellose sodium(Ac-Di-Sol) 24 SBE₇-γCD 118 Microcrystalline cellulose (Avicel PH102)150 Colloidal silicon dioxide (Cab-O-Sil) 1.5 Magnesium stearate 1.5Total 300

All tablet ingredients are sieved through 40-mesh screen (US Standard)prior to weighing, and then all ingredients except magnesium (Mg)stearate are mixed in a glass bottle using a geometric dilutiontechnique. The powder blend is then passed through the 40-mesh screentwice to facilitate homogenous mixing of all ingredients. Prior tomechanical compression, Mg stearate is added and then mixed for anadditional minute. Lastly, the final blend is compressed into tabletswith 7-mm concave tooling using a rotary tablet press to give a tablethardness of approximately 3.0 kiloponds (kp).

Example 13

A constitutable powdered formulation of lamotrigine and a SAE-CDcomposition, sulfobutyl ether-beta-cyclodextrin with an average degreeof substitution of 7 (SBE₇-PCD), was prepared using the followingformula.

Ingredient Amount (g) Lamotrigine 7.50 SBE₇-βCD 37.5 Citric Acid USP3.75 Xylitol 300 Sodium Saccharin 0.75 Benzoic acid 1.28 StrawberryFlavor 1.4 Xanthan gum 1.5 Total 353.68

The sodium saccharin, benzoic acid, strawberry flavor, citric acid, andxanthan gum are combined together and mixed well. The lamotrigine isadded to the blend with further mixing then the SBE₇-PCD is added andmixing is continued. The xylitol is then added to the resulting powderwith geometric dilution and further mixing.

The powder can be constituted with water to give a final volume of 750mL.

The following terms are defined as detailed below.

TERM DEFINITION Agglomerate A collection of particles that are fusedtogether and act as a larger particle. Bulk density Mass of bulk powderdivided by the bulk volume Carr's Index Measure of the bulk flowproperties of powders. CD Cyclodextrin DPI Dry powder inhaler KF KarlFisher Analysis MDI Metered dose inhaler, or more correctly, propellantdriven metered dose inhaler monodisperse In terms of particle size,refers to a population of particles that have a uniform particle size nCnanoCoulomb, measure of charge ND Not determined pMDI pressurizedmetered dose inhaler SEM Scanning electron microscope Tapped densityMass of bulk powder divided by the volume of packed powder (followingcompaction of the powder by vertical tapping)

As used herein, the term “about” means+/−10% of the value indicated.

The above is a detailed description of particular embodiments of theinvention. It will be appreciated that, although specific embodiments ofthe invention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims. All of the embodiments disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure. The disclosure of any patent or otherpublication cited herein is incorporated herein by reference.

The invention claimed is:
 1. A pharmaceutical composition comprising asulfoalkyl ether cyclodextrin composition and an active agent, whereinthe sulfoalkyl ether cyclodextrin composition comprises: (a) sulfoalkylether cyclodextrin; and (b) no more than about 20% by weight moisture;and wherein the sulfoalkyl ether cyclodextrin composition has a bulkdensity of about 0.38 g/cm³ to about 0.66 g/cm³ and a tapped density ofabout 0.49 g/cm³ to about 0.75 g/cm³, wherein the tapped density of thesulfoalkyl ether cyclodextrin composition is higher than the bulkdensity; and a gravitational-flow minimum orifice diameter of about 3 mmto about 12 mm; and wherein the sulfoalkyl ether cyclodextrincomposition comprises agglomerated particles; and wherein the activeagent is an antibiotic agent, an antihistamine agent, a decongestant, ananti-inflammatory agent, an antiparasitic agent, an antiviral agent, alocal anesthetic, an antifungal agent, an antibacterial agent, anamoebicidal agent, a trichomonocidal agent, an analgesic agent, ananti-arthritic agent, an anti-asthmatic agent, an anticoagulant agent,an anticonvulsant agent, an antidepressant agent, an antidiabetic agent,an antineoplastic agent, an anti-psychotic agent, a neuroleptic agent,an antihypertensive agent, a hypnotic agent, a sedative agent, ananxiolytic energizer agent, an anti-Parkinson's disease agent, ananti-Alzheimer's disease agent, a muscle relaxant agent, an antimalarialagent, a hormonal agent, a contraceptive agent, a sympathomimetic agent,a hypoglycemic agent, an anti-hyperglyceridemia agent, ananti-dyslipidemia agent, a cholesterol reducing agent, a bile acidabsorption inhibitor, an antilipemic agent, an ophthalmic agent, anelectrolytic agent, a diagnostic agent, a prokinetic agent, a gastricacid secretion inhibitor agent, an anti-ulcerant agent, ananti-flatulent agent, an anti-incontinence agent, a cardiovascularagent, a corticosteroid, a B2 adrenoreceptor agonist, a dopamine D2receptor agonist, an anticholinergic agent, an IL-5 inhibitor, anantisense modulators of IL-5, milrinone lactate, tryptase inhibitor,tachykinin receptor antagonist, leukotriene receptor antagonist,5-lypoxygenase inhibitor, anti-IgE antibody, protease inhibitor or anycombinations thereof.
 2. The composition of claim 1, wherein the tappeddensity is in the range of 0.66 g/cm³ to about 0.75 g/cm³.
 3. Thecomposition of claim 1, wherein the bulk density is in the range of 0.55g/cm³ to about 0.66 g/cm³.
 4. The composition of claim 1, wherein theactive agent is an anticholinergic agent.
 5. The composition of claim 4,wherein the anticholinergic agent is tiotropium, ipratropium, oxitropiumor glycopyrronium.
 6. The composition of claim 1, wherein the activeagent is an leukotriene antagonist.
 7. The composition of claim 6,wherein the leukotriene antagonist is andolast, iralukast, pranlukast,imitrodast, seratrodast, zileuton, zafirlukast or montelukast.
 8. Thecomposition of claim 1, wherein the active agent is a phosphodiesteraseinhibitor.
 9. The composition of claim 8, wherein the phosphodiesteraseinhibitor is filaminast or piclamilast montelukast.
 10. The compositionof claim 1, wherein the sulfoalkyl ether cyclodextrin is a compound, ora mixture of compounds, of the Formula 1:

wherein: n is 4, 5, or 6; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉ areeach, independently, O⁻ or a O—(C₂₋₆ alkylene)-SO₃ ⁻ group, wherein atleast one of R₁ and R₂ is, independently, the O—(C₂-C₆ alkylene)-SO₃ ⁻group; and S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈, and S₉, are each,independently, a pharmaceutically acceptable cation.
 11. The compositionof claim 1, wherein the sulfoalkyl ether cyclodextrin composition has aCARR's index of about 18% or less.
 12. The composition of claim 1,wherein the sulfoalkyl ether cyclodextrin composition has a CARR's indexof about 24% or less.
 13. The composition of claim 1, wherein thesulfoalkyl ether cyclodextrin composition comprises particles with amean particle diameter of about 75 microns to about 200 microns.
 14. Apharmaceutical composition comprising a sulfoalkyl ether cyclodextrincomposition and an active agent, wherein the sulfoalkyl ethercyclodextrin composition comprises: (a) sulfoalkyl ether cyclodextrin;(b) no more than about 20% by weight moisture; and wherein thesulfoalkyl ether cyclodextrin composition has a bulk density of about0.38 g/cm³ to about 0.66 g/cm³ and a tapped density of about 0.49 g/cm³to about 0.75 g/cm³, wherein the tapped density of the sulfoalkyl ethercyclodextrin composition is higher than the bulk density; and agravitational-flow minimum orifice diameter of about 3 mm to about 12mm; and wherein the sulfoalkyl ether cyclodextrin composition comprisesagglomerated particles; and wherein the active agent is pentamidineisethiouate, albuterol sulfate, metaproterenol sulfate, flunisolide,cromolyn sodium, sodium cromoglycate, ergotamine tartrate, levalbuterol,terbutaline, reproterol, salbutamol, salmeterol, formoterol, fenoterol,clenbuterol, bambuterol, tulobuterol, broxaterol, epinephrine,isoprenaline hexoprenaline, or a combination thereof.
 15. Thecomposition of claim 14, wherein the tapped density is in the range of0.66 g/cm³ to about 0.75 g/cm³.
 16. The composition of claim 14, whereinthe bulk density is in the range of 0.55 g/cm³ to about 0.66 g/cm³. 17.The composition of claim 1, wherein the sulfoalkyl ether cyclodextrin isa compound, or a mixture of compounds, of the Formula 1:

wherein: n is 4, 5, or 6; R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉ areeach, independently, O⁻ or a O—(C₂₋₆ alkylene)-SO₃ ⁻ group, wherein atleast one of R₁ and R₂ is, independently, the O—(C₂-C₆ alkylene)-SO₃ ⁻group; and S₁, S₂, S₃, S₄, S₅, S₆, S₇, S₈, and S₉, are each,independently, a pharmaceutically acceptable cation.
 18. The compositionof claim 1, wherein the sulfoalkyl ether cyclodextrin composition has aCARR's index of about 18% or less.
 19. The composition of claim 1,wherein the sulfoalkyl ether cyclodextrin composition has a CARR's indexof about 24% or less.
 20. The composition of claim 15, wherein thesulfoalkyl ether cyclodextrin composition comprises particles with amean particle diameter of about 75 microns to about 200 microns.